Therapeutic Methods For Type I Diabetes

ABSTRACT

The invention relates to the treatment and prevention of type I diabetes. More specifically, the invention relates to compounds that treat or prevent the body&#39;s immune system from destroying β-cells (i.e., insulin-producing cells in the pancreatic islets of Langerhans) by inhibition of JNK2, selective inhibition of JNK2, or inhibition of the expression of the MAPK9 gene or gene product. In one embodiment, the present invention contemplates the diagnosis, identification, production, and use of compounds which modulate MAPK9 gene expression or the activity of the MAPK9 gene product including but not limited to, JNK2, the nucleic acid encoding MAPK9 and homologues, analogues, and deletions thereof, as well as antisense, ribozyme, triple helix, antibody, and polypeptide molecules as well as small inorganic molecules. The present invention contemplates a variety of pharmaceutical formulations and routes of administration for such compounds.

BACKGROUND

Insulin made in the pancreas is necessary for the body to be able to usesugar as fuel. Insulin signals the intake of sugar (i.e., glucose) fromthe blood into cells of the body (e.g., muscles). In type I diabetes,the pancreas no longer produces insulin; so, patients with type Idiabetes need to take insulin shots in order to compensate for thepancreas' inability to produce insulin. Conditions associated with typeI diabetes include hypoglycemia, ketoacidosis and celiac disease. Havingtype I diabetes increases your risk for many serious complicationsincluding: heart disease (cardiovascular disease), blindness(retinopathy), nerve damage (neuropathy), and kidney damage(nephropathy). The insulin shortage in type I diabetes is believed to becaused by an autoimmune process in which the body's immune systemdestroys the β-cells in the pancreas. Thus, there is a need to identifymethods of treating and preventing type I diabetes by preventing thebody's immune system from destroying β-cells in the pancreas.

SUMMARY OF THE INVENTION

The invention relates to the treatment and prevention of type Idiabetes. More specifically, the invention relates to compounds thattreat or prevent the body's immune system from destroying β-cells (i.e.,insulin-producing cells in the pancreatic islets of Langerhans) byinhibition of JNK2, selective inhibition of JNK2, or inhibition of theexpression of the MAPK9 gene or gene product. In one embodiment, thepresent invention contemplates the diagnosis, identification,production, and use of compounds which modulate MAPK9 gene expression orthe activity of the MAPK9 gene product including but not limited to,JNK2, the nucleic acid encoding MAPK9 and homologues, analogues, anddeletions thereof, as well as antisense, ribozyme, triple helix,antibody, and polypeptide molecules as well as small inorganicmolecules. The present invention contemplates a variety ofpharmaceutical formulations and routes of administration for suchcompounds.

In one embodiment, the invention is a method for treating type Idiabetes in a subject, comprising administering a compound that inhibitsactivity of JNK2 in the subject. In further embodiments, the compoundinhibits the enzymatic activity of JNK2, and has minimal effect onenzymatic activity of JNK1. In further embodiments, the activity of JNK1is not inhibited.

It is not intended that the present invention be limited to completeinhibition of JNK2. For example, it is sufficient that the inhibitor hasan IC₅₀ of less than 10 mM in a c-jun phosphorylation assay describedbelow. Inhibition can be measured in vitro or in vivo. In vitroinhibition is readily measured in a variety of assays (an example ofwhich is provided below). Inhibition in vivo is established by theobservation of reduced insulitis (e.g. a reduction in non-diabetic obesemice islets showing invasive, destructive, or peri-insulitis of 10% ormore as measured by a histological analysis of the pancreas).

In another embodiment, the invention is a method for treating type Idiabetes in a subject, comprising administering a compound thatselectively inhibits activity of JNK2 compared to JNK1 in a subject,wherein the activity of the compound does not result in adverse drugreactions to the subject. It is not intended that the present inventionbe limited to complete absence of adverse drug reactions in the subject.

In another embodiment, the invention is a method of treating type Idiabetes in a subject, comprising administering an antisenseoligonucleotides of MAPK9 that inhibits the expression of JNK2. Infurther embodiments, the antisense oligonucleotide of JNK2 inhibits theexpression of JNK2, and has minimal effect on the expression of JNK1.

In another embodiment, the invention is a method of treating type Idiabetes in a subject, comprising administering an amino acid sequencewithin JIP-1 or JIP-2 that inhibits the activity of JNK2 in the subject(i.e. a portion preferably comprising at least 10 amino acids and morepreferably at least 18). In further embodiments, the amino acid sequencehas a minimal effect on the enzymatic activity of JNK1.

In another embodiment, the invention is a method of treating type Idiabetes in a subject, comprising administering a compound of thefollowing formula:

wherein: Ar¹ is a substituted or unsubstituted aryl or heteroaryl group;X is O or S; Ar² a substituted or unsubstituted aryl or heteroarylgroup; R¹ and R² are independently selected from the group consisting ofhydrogen and a C₁-C₆-alkyl group; R^(a), R^(a′), R^(b), R^(b′) areindependently selected from the group consisting of hydrogen andC₁-C₆-alkyl; or R^(a′) and R^(a) or R^(b′) together with the carbonatoms they are linked, form a substituted or unsubstituted 5-8-memberedsaturated, partially unsaturated or aromatic ring containing optionallyone or more heteroatoms selected from O, N, S; R³ is selected from thegroup consisting of H, C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkynyl,aryl, heteroaryl, 3-8 membered cycloalkyl optionally containing 1-3heteroatoms selected from the group consisting of N, O, and S; arylC₁-C₁₀-alkyl and heteroaryl C₁-C₁₀-alkyl; or R³ and R^(a) or R^(a′)form, together with the N atom linked to R³, a 5-8-membered saturatedring, containing optionally at least one further heteroatom selectedfrom O, N, S; R⁴ is selected from the group consisting of H and—C(H)R⁵R⁶; R⁵ and R⁶ are independently selected from the groupconsisting of H, C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkynyl, aryl,heteroaryl, 3-8 membered cycloalkyl optionally containing 1-3heteroatoms selected from the group consisting of N, O, and S; arylC₁-C₁₀-alkyl and heteroaryl C₁-C₁₀-alkyl; m is an integer from 1 to 5; nis an integer from 0 to 2; and p is an integer from 1 to 10; thatinhibits the activity of JNK2 in the subject. In further embodiments,the compound has a minimal effect on the enzymatic activity of JNK1.

In another embodiment, the invention is a method of treating type Idiabetes in a subject, comprising administering a compound of thefollowing formula:

wherein Ar¹ and Ar² are independently from each other substituted orunsubstituted aryl or heteroaryl groups; X is O or S; R¹ is hydrogen ora C₁-C₆ alkyl group, or R¹ forms a substituted or unsubstituted 5-6membered saturated or unsaturated ring with Ar¹; n is an integer from 0to 5, preferably between 1-3 and most preferred 1; Y is an unsubstitutedor a substituted 4-12 membered saturated cyclic or bicyclic alkylcontaining at least one nitrogen atom, whereby one nitrogen atom withinsaid ring is forming a bond with the sulfonyl group thus providing asulfamide: that inhibits the activity of JNK2 in the subject. In furtherembodiments, the compound has a minimal effect on the enzymatic activityof JNK1.

In another embodiment, the invention is a method of treating type Idiabetes in a subject, comprising administering a compound of thefollowing formula:

wherein Ar¹ and Ar² are independently from each other substituted orunsubstituted aryl or heteroaryl; X is O or S; R¹ is hydrogen or anunsubstituted or substituted C₁-C₆-alkyl group, or R¹ could form asubstituted or unsubstituted 5-6-membered saturated or unsaturated fusedring with Ar¹, or R² and R⁴ form a substituted or unsubstituted5-6-membered saturated or non-saturated ring; R² is hydrogen or asubstituted or unsubstituted C₁-C₆-alkyl group; n is an integer from 0to 5; R³ and R⁴ are independently from each other selected from thegroup comprising or consisting of natural amino acid residues orsynthetic amino acid residues, hydrogen, substituted or unsubstitutedC₁-C₆-alkyl, like trihalomethyl, substituted or unsubstitutedC₁-C₆-alkoxy, NH₂, SH, thioalkyl, aminoacyl, aminocarbonyl, substitutedor unsubstituted C₁-C₆-alkoxycarbonyl, aryl, heteroaryl, substituted orunsubstituted 4-8-membered cyclic alkyl, optionally containing 1-3heteroatoms, carboxyl, cyano, halogen, hydroxy, nitro, acetoxy,aminoacyl, sulfoxy, sulfonyl, C₁-C₆-thioalkoxy, whereby at least one ofR³ and/or R⁴ must be an amino acid residue; R^(s) is H or substituted orunsubstituted C₁-C₆-alkyl; R⁶ is selected from the group comprising orconsisting of H, substituted or unsubstituted C₁-C₆-aliphatic alkyl,substituted or unsubstituted saturated cyclic C₄-C₈-alkyl optionallycontaining 1-3 heteroatoms and optionally fused with an aryl or anheteroaryl; or R⁶ is a substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, whereby said aryl or heteroaryl groups areoptionally substituted with substituted or unsubstituted C₁-C₆-alkyl,like trihalomethyl, substituted or unsubstituted C₁-C₆-alkoxy,substituted or unsubstituted C₂-C₆-alkenyl, substituted or unsubstitutedC₂-C₆-alkynyl, amino, aminoacyl, aminocarbonyl, substituted orunsubstituted C₁-C₆-alkoxycarbonyl, aryl, carboxyl, cyano, halogen,hydroxy, nitro, acetoxy, aminoacyl, sulfoxy, sulfonyl, C₁-C₆-thioalkoxy;or R⁵ and R⁶ taken together could form a substituted or unsubstituted4-8-membered saturated cyclic alkyl or heteroalkyl group; that inhibitsthe activity of JNK2 in the subject. In further embodiments, thecompound has a minimal effect on the enzymatic activity of JNK1.

In another embodiment, the invention is a method of treating type Idiabetes in a subject, comprising administering a compound of thefollowing formula:

wherein Ar¹ and Ar² are independently from each other substituted orunsubstituted aryl or heteroaryl groups; X¹ and X² are independentlyfrom each other O or S; R¹, R², and R³ are independently from each otherhydrogen or a C₁-C₆ alkyl substituent or R¹ forms a substituted orunsubstituted 5-6-membered saturated or unsaturated ring with Ar¹; or R²and R³ form a substituted or unsubstituted 5-6-membered saturated orunsaturated ring; n is an integer from 0 to 5; G is selected from agroup comprising or consisting of an unsubstituted or substituted4-8-membered heterocycle containing at least one heteroatom, or G is asubstituted or unsubstituted C₁-C₆ alkyl group; that inhibits theactivity of JNK2 in the subject. In further embodiments, the compoundhas a minimal effect on the enzymatic activity of JNK1.

In another embodiment, the invention is a method of treating type Idiabetes in a subject, comprising administering a compound of thefollowing formula:

wherein Z¹¹ and Z¹² each independently represent a carbonyl group, anoxygen atom, a sulfur atom, a methine group which may be substituted, amethylene group which may be substituted or a nitrogen atom which may besubstituted;

represents a double bond or a single bond; R^(a) represents a hydrogenatom, a C₁-C₆ alkyl group, a phenyl group or a benzyl group; R^(2a),R^(2b) and R^(2c) each independently represent a group selected from thefollowing Substituent Group (a); the ring A represents a benzene ringwhich may have one to three groups selected from the followingSubstituent Group (a), a naphthalene ring which may have one to threegroups selected from the following Substituent Group (a) or a 5- to10-membered aromatic heterocyclic ring which may have one to threegroups selected from the following Substituent Group (a); SubstituentGroup (a) (1) a hydrogen atom, (2) halogen atoms, (3) a nitro group, (4)a hydroxyl group, (5) a cyano group, (6) a carboxyl group, (7) an aminogroup, (8) a formyl group or (9) a group represented by the formula:

wherein X¹ and X² each independently represent a single bond, —CO—,—SO₂— or C₁-C₆-methylene group; X³ represents a single bond, —CO—, —SO₂,—O—, —CO—O— or —O—CO—; R^(3b) represents a C₁-C₆ alkylene group or asingle bond; R^(3a) and R^(3c) represent a hydrogen atom, a C₁-C₆ alkylgroup which may be substituted, a C₂-C₆ alkenyl group which may besubstituted, a C₂-C₆ alkynyl group which may be substituted, a C₃-C₈cycloalkyl group which may be substituted, a C₆-C₁₄ aromatic cyclichydrocarbon group which may be substituted, a 5- to 14-membered aromaticheterocyclic group which may be substituted or a hydrogen atom; thatinhibits the activity of JNK2 in the subject. In further embodiments,the compound has a minimal effect on the enzymatic activity of JNK1.

In another embodiment, the invention is a method of treating type Idiabetes in a subject, comprising administering a compound of thefollowing formula:

wherein A is a direct bond, —(CH₂)_(a)—, —(CH₂)_(b)CH═CH(CH₂)_(c)—, or—(CH₂)_(b)C≡C(CH₂)_(c)—; R¹ is aryl, heteroaryl or heterocycle fused tophenyl, each being optionally substituted with one to four substituentsindependently selected from R³; R² is —R³, —R⁴, —(CH₂)_(b)C(═O)R⁵,—(CH₂)_(b)C(═O)OR⁵, —(CH₂)_(b)C(═O)NR⁵R⁶,—(CH₂)_(b)C(═O)NR₅(CH₂)CC(═O)R⁶, —(CH₂)_(b)NR⁵C(═O)R⁶,—(CH₂)_(b)NR⁵C(═O)NR⁶R⁷, —(CH₂)_(b)NR⁵R⁶, —(CH₂)_(b)OR⁵,—(CH₂)_(b)SO_(d)R⁵ or —(CH₂)_(b)SO₂NR⁵R⁶; a is 1, 2, 3, 4, 5 or 6; b andc are the same or different and at each occurrence independentlyselected from 0, 1, 2, 3 or 4; d is at each occurrence 0, 1 or 2; R³ isat each occurrence independently halogen, hydroxy, carboxyl, alkyl,alkoxy, haloalkyl, acyloxy, thioalkyl, sulfinylalkyl, sulfonylalkyl,hydroxyalkyl, aryl, arylalkyl, heterocycle, heterocycloalkyl, —C(═O)OR⁸,—OC(═O)R⁸, —C(═O)NR⁸R⁹, —C(═O)NR⁸OR⁹, —SO₂NR⁸R⁹, —NR⁸SO₂R⁹, —CN, —NO₂,—NR⁸R⁹, —NR⁸C(═O)R⁹, —NR⁸C(═O)(CH₂)_(b)OR⁹, —NR⁸C(═O)(CH₂)_(b)R⁹,—O(CH₂)_(b)NR⁸R⁹, or heterocycle fused to phenyl; R⁴ is alkyl, aryl,arylalkyl, heterocycle or heterocycloalkyl, each being optionallysubstituted with one to four substituents independently selected fromR³, or R⁴ is halogen or hydroxy; R⁵, R⁶ and R⁷ are the same or differentand at each occurrence independently hydrogen, alkyl, aryl, arylalkyl,heterocycle or heterocycloalkyl, wherein each of R⁵, R⁶ and R⁷ areoptionally substituted with one to four substituents independentlyselected from R³; and R⁸ and R⁹ are the same or different and at eachoccurrence independently hydrogen, alkyl, aryl, arylalkyl, heterocycle,or heterocycloalkyl, or R⁸ and R⁹ taken together with the atom or atomsto which they are bonded form a heterocycle, wherein each of R⁸, R⁹, andR⁸ and R⁹ taken together to form a heterocycle are optionallysubstituted with one to four substituents independently selected fromR³; that inhibits the activity of JNK2 in the subject. In furtherembodiments, the compound has a minimal effect on the enzymatic activityof JNK1.

In another embodiment, the invention is a method of treating type Idiabetes in a subject, comprising administering a compound of thefollowing formula:

wherein R¹ is aryl or heteroaryl optionally substituted with one to foursubstituents independently selected from R⁷; R² is hydrogen; R³ ishydrogen or lower alkyl; R⁴ represents one to four optionalsubstituents, wherein each substituent is the same or different andindependently selected from halogen, hydroxy, lower alkyl and loweralkoxy; R⁵ and R⁶ are the same or different and independently —R⁸,—(CH₂)_(a)C(═O)R⁹, —(CH2)_(a)C(═O)OR⁹, —(CH2)_(a)C(═O)NR⁹R¹⁰,—(CH2)_(a)C(═O)NR⁹(CH2)_(b)C(═O)R¹⁰, —(CH2)_(a)NR⁹C(═O)R¹⁰,(CH2)_(a)NR¹¹C(═O)NR⁹R¹⁰, —(CH2)_(a)NR⁹R¹⁰, —(CH2)_(a)OR⁹,—(CH2)_(a)SO_(c)R⁹ or —(CH2)_(n)SO2NR⁹R¹⁰; or R⁵ and R⁶ taken togetherwith the nitrogen atom to which they are attached to form a heterocycleor substituted heterocycle; R⁷ is at each occurrence independentlyhalogen, hydroxy, cyano, nitro, carboxyl, alkyl, alkoxy, haloalkyl,acyloxy, thioalkyl, sulfinylalkyl, sulfonylalkyl, hydroxyalkyl, aryl,arylalkyl, heterocycle, substituted heterocycle, heterocycloalkyl,—C(═O)OR⁸, —OC(═O)R⁸, —C(═O)NR⁸R⁹, —C(═O)NR⁸OR⁹, —SO_(c)R⁸,—SO_(c)NR⁸R⁹, —NR⁸SOR⁹, —NR⁸R⁹, —NR⁸C(═O)R⁹, —NR⁸C(═O)(CH₂)bOR⁹,—NR⁸C(═O)(CH2)_(b)R⁹, —O(CH2)_(b)NR⁸R⁹, or heterocycle fused to phenyl;R⁸, R⁹, R¹⁰ and R¹¹ are the same or different and at each occurrenceindependently hydrogen, alkyl, aryl, arylalkyl, heterocycle,heterocycloalkyl; or R⁸ and R⁹ taken together with the atom or atoms towhich they are attached to form a heterocycle; a and b are the same ordifferent and at each occurrence independently selected from 0, 1, 2, 3or 4; and c is at each occurrence 0, 1 or 2; that inhibits the activityof JNK2 in the subject. In further embodiments, the compound has aminimal effect on the enzymatic activity of JNK1.

In another embodiment, the invention is a method of treating type Idiabetes in a subject, comprising administering a compound of thefollowing formula:

wherein R⁰ is —O—, —S—, —S(O)—, —S(O)₂—, NH or —CH₂—; being: (i)unsubstituted, (ii) monosubstituted and having a first substituent, or(iii) disubstituted and having a first substituent and a secondsubstituent; the first or second substituent, when present, is at the 3,4, 5, 7, 8, 9, or 10 position, wherein the first and second substituent,when present, are independently alkyl, hydroxy, halogen, nitro,trifluoromethyl, sulfonyl, carboxyl, alkoxycarbonyl, alkoxy, aryl,aryloxy, arylalkyloxy, arylalkyl, cycloalkylalkyloxy, cycloalkyloxy,alkoxyalkyl, alkoxyalkoxy, aminoalkoxy, mono-alkylaminoalkoxy,di-alkylaminoalkoxy, —NHR³R⁴, —NH(CH₂)_(n)NR³R⁴, —NH(═O)R⁵, —NHSO₂R⁵,—C(═O)NR³R⁴, or —SO₂NR³R⁴; wherein n is 0-6, R³ and R⁴ are takentogether and represent alkylidene or a heteroatom-containing cyclicalkylidene or R³ and R⁴ are independently hydrogen, alkyl, cycloalkyl,aryl, arylalkyl, cycloalkylalkyl, aryloxyalkyl, alkoxyalkyl, aminoalkyl,mono-alkylaminoalkyl, or di-alkylaminoalkyl; and R⁵ is hydrogen, alkyl,cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl,alkoxycarbonylalkyl, amino, mono-alkylamino, di-alkylamino, arylamino,arylalkylamino, cycloalkylamino, cycloalkylalkylamino, aminoalkyl,mono-alkylaminoalkyl, or di-alkylaminoalkyl; that inhibits the activityof JNK2 in the subject.

In further embodiments, the compound has a minimal effect on theenzymatic activity of JNK1.

In another embodiment, the invention is a method of treating type Idiabetes in a subject, comprising administering a compound of thefollowing formula:

wherein N¹ is a nitrogen atom optionally having a substituent or ahydrogen atom, X¹ is (i) a carbon atom optionally having substituent(s)or hydrogen atom(s), (ii) an oxygen atom, (iii) a sulfur atom or (iv) anitrogen atom optionally having a substituent or a hydrogen atom, X² is(i) a carbon atom optionally having substituent(s) or hydrogen atom(s),(ii) an oxygen atom, (iii) a sulfur atom or (iv) a nitrogen atomoptionally having a substituent or a hydrogen atom, X³ is (i) a carbonatom or (ii) a nitrogen atom, wherein (1) when X¹ is an oxygen atom or asulfur atom, X² is a carbon atom optionally having substituent(s) orhydrogen atom(s), X³ is a carbon atom and N¹ is a nitrogen atom, (2)when X¹ is a nitrogen atom having a substituent or a hydrogen atom andX³ is a carbon atom, X2 is a carbon atom optionally havingsubstituent(s) or hydrogen atom(s) and N¹ is a nitrogen atom, (3) when.X¹ and X³ are each a nitrogen atom, X² is a carbon atom optionallyhaving substituent(s) or hydrogen atom(s), and N¹ is a nitrogen atom,(4) when X¹ is a carbon atom optionally having substituent(s) orhydrogen atom(s) and X² is an oxygen atom or a sulfur atom, X³ is acarbon atom and N¹ is a nitrogen atom, (5) when X¹ is a carbon atomoptionally having substituent(s) or hydrogen atom(s) and X³ is a carbonatom, one of N¹ and X² is a nitrogen atom, and the other is a nitrogenatom having a substituent or a hydrogen atom, (6) when X¹ and X² areeach a carbon atom optionally having substituent(s) or hydrogen atom(s)and X³ is a carbon atom, N¹ is a nitrogen atom having a substituent or ahydrogen atom, and (7) when X¹ and X² are each a carbon atom optionallyhaving substituent(s) or hydrogen atom(s) and X³ is a nitrogen atom, N¹is a nitrogen atom, ring A optionally further has substituent(s), ring Bis an aromatic ring, Y is (i) a carbon atom optionally havingsubstituent(s) or hydrogen atom(s) or (ii) a nitrogen atom, Z is a bond,—NR⁴—(R⁴ is a hydrogen atom or a hydrocarbon group optionally havingsubstituent(s)), an oxygen atom or an optionally oxidized sulfur atom, Wis a bond or a divalent hydrocarbon group optionally havingsubstituent(s), R² is an aromatic group optionally havingsubstituent(s), and R³ is a hydrocarbon group optionally havingsubstituent(s) or a heterocyclic group optionally having substituent(s);that inhibits the activity of JNK2 in the subject. In furtherembodiments, the compound has a minimal effect on the enzymatic activityof JNK1.

In another embodiment, the invention is a method of treating type Idiabetes in a subject, comprising administering a compound of thefollowing formula:

wherein: W is nitrogen or CH; G is hydrogen or C₁₋₃ aliphatic whereinone methylene unit of G is optionally replaced by —C(O)—, —C(O)O—,—C(O)NH—, —SO₂—, or —SO₂NH—; A is —N-T_((n))-R, oxygen, or sulfur; R¹ isselected from -T_((n))-R or -T_((n))-Ar¹; each n is independently 0 or1; T is a C₁₋₄ alkylidene chain wherein one methylene unit of T isoptionally replaced by —C(O)—, —C(O)O—, —C(O)NH—, —SO₂—, or —SO₂NH—; Ar¹is a 3-7 membered monocyclic saturated, partially saturated or aromaticring having 0-3 heteroatoms independently selected from nitrogen,oxygen, or sulfur, or a 8-10 membered bicyclic saturated, partiallysaturated or aromatic ring having 0-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, wherein each member of Ar¹ isoptionally substituted with one —Z—R³ and one to three additional groupsindependently selected from —R, halogen, oxo, —NO₂, —CN, —OR, —SR,—N(R)₂, —NRC(O)R, —NRC(O)N(R)₂, —NRCO₂R, —C(O)R, —CO₂R, —OC(O)R,—C(O)N(R)₂, —OC(O)N(R)₂, —S(O)R, —SO₂R, —SO₂N(R)₂, —NRSO₂R, —NRSO₂N(R)₂,—C(O)C(O)R, or —C(O)CH₂C(O)R; each R is independently selected fromhydrogen or a C₁₋₆ aliphatic, wherein said aliphatic is optionallysubstituted with one to three groups independently selected from oxo,—CO₂R′, —OR′, —N(R′)₂, —SR′, —NO₂, —NR′C(O)R′, —NR′C(O)N(R′)₂,—NR′CO₂R′, —C(O)R′, —OC(O)R′, —C(O)N(R′)₂, —OC(O)N(R′)₂, —S(O)R′,—SO₂R′, —SO₂N(R′)₂, —NR′SO₂R′, —NR′SO₂N(R′)₂, —C(O)C(O)R′,—C(O)CH₂C(O)R′, halogen, or —CN, or two R bound to the same nitrogenatom are taken together with that nitrogen atom to form a five or sixmembered heterocyclic or heteroaryl ring having one to two additionalheteroatoms independently selected from oxygen, nitrogen, or sulfur;each R′ is independently selected from hydrogen or C₁₋₆ aliphatic,wherein said aliphatic is optionally substituted with one to threegroups independently selected from oxo, —CO₂H, —OH, —NH₂, —SH, —NO₂,—NHC(O)H, —NHC(O)NH₂, —NHCO₂H, —C(O)H, —OC(O)H, —C(O)NH₂, —OC(O)NH₂,—S(O)H, —SO₂H, —SO₂NH₂, —NHSO₂H, —NHSO₂NH₂, —C(O)C(O)H, —C(O)CH₂C(O)H,halogen, or —CN, or two R′ bound to the same nitrogen atom are takentogether with that nitrogen atom to form a five or six memberedheterocyclic or heteroaryl ring optionally having one or two additionalheteroatoms independently selected from nitrogen, oxygen, or sulfur; Zis a C₁-C₆ alkylidene chain wherein up to two nonadjacent methyleneunits of Z are optionally replaced by —C(O)—, —C(O)O—, —C(O)C(O)—,—C(O)N(R)—, —OC(O)N(R)—, —N(R)N(R)—, —N(R)N(R)C(O)—, —N(R)C(O)—,—N(R)C(O)O—, —N(R)C(O)N(R)—, —S(O)—, —SO₂—, —N(R)SO₂—, —SO₂N(R)—,—N(R)SO₂N(R)—, —O—, —S—, or —N(R)—; R² is -Q_((n))-Ar²; Ar² is selectedfrom a 3-7 membered monocyclic saturated, saturated or aromatic ringhaving 0-3 heteroatoms independently selected from nitrogen, oxygen, orsulfur, or a 8-10 membered bicyclic saturated, saturated or aromaticring having 0-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur, wherein each member of Ar² is optionally substitutedwith 1-5 groups independently selected from —Z—R³, —R, halogen, oxo,—NO2, —CN, —OR, —SR, —N(R)₂, NRC(O)R, —NRC(O)N(R)₂, —NRCO₂R, —C(O)R,—CO₂R, OC(O)R, —C(O)N(R)₂, —OC(O)N(R)₂, —S(O)R, —SO₂R, SO₂N(R)₂,—N(R)SO₂R, —N(R)SO₂N(R)₂, —C(O)C(O)R, or —C(O)CH₂C(O)R; Q is a C₁₋₃alkylidene chain wherein up to two nonadjacent methylene units of Q areoptionally replaced by —C(O)—, —C(O)O—, —C(O)C(O)—, —C(O)N(R)—,—OC(O)N(R)—, —N(R)N(R)—, —N(R)N(R)C(O)—, —N(R)C(O)—, —N(R)C(O)O—,—N(R)C(O)N(R)—, —S(O)—, —SO₂—, —N(R)SO₂—, —SO₂N(R)—, —N(R)SO₂N(R)—, —O—,—S—, or —N(R)—; R³ is selected from —Ar³, —R, halogen, —NO₂, —CN, —OR,—SR, —N(R)₂, —NRC(O)R, —NRC(O)N(R)₂, —NRCO₂R, —C(O)R, —CO₂R, —OC(O)R,—C(O)N(R)₂, —OC(O)N(R)₂, —SOR, —SO₂R, —SO₂N(R)₂, —NRSO₂R, —NRSO₂N(R)₂,—C(O)C(O)R, or —C(O)CH2C(O)R; and Ar³ is a 5-6 membered saturated,partially saturated, or aromatic ring having 0-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, wherein eachmember of Ar³ is optionally substituted with halogen, oxo, —CN, —NO₂,—R′, —OR′, —N(R′)₂, —N(R′)C(O)R′, N(R′)C(O)N(R′)₂, —N(R′)CO₂R′, —C(O)R′,—CO₂R′, OC(O)R′, —C(O)N(R′)₂, —OC(O)N(R′)₂, or —SO₂R′; provided thatwhen W is nitrogen and: (i) A is —N-T_((n))-R and R2 is a saturated ringor (ii) A is sulfur, then R¹ is other than an optionally substitutedphenyl; that inhibits the activity of JNK2 in the subject. In furtherembodiments, the compound has a minimal effect on the enzymatic activityof JNK1.

In another embodiment, the invention is a method of treating type Idiabetes in a subject, comprising administering a compound of thefollowing formula:

wherein R¹ is optionally substituted carbocyclyl or heterocyclyl group,R² is an optionally substituted five or six membered heterocyclyl groupor an optionally substituted six membered carbocyclyl group, E ishydrogen, halogen cyano, C₁₋₆ alkoxy or C₁₋₆ alkyl, G is hydrogen,halogen, cyano, C₁₋₆ alkoxy or C₁₋₆ alkyl, and L is hydrogen, halogen,cyano, C₁₋₆ alkoxy or C₁₋₆ alkyl; that inhibits the activity of JNK2 inthe subject. In further embodiments, the compound has a minimal effecton the enzymatic activity of JNK1.

In another embodiment, the invention is a method of treating type Idiabetes in a subject, comprising administering a compound of thefollowing formula:

wherein R¹ is an optionally substituted C₃₋₁₆ carbocyclyl or C₃₋₁₂heterocyclyl group, Y is N or C and Z is lone electron pair, hydrogen,C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₁₋₁₂ haloalkyl, C₃₋₁₂carbocyclyl, C₃₋₁₂ heterocyclyl, —(CH₂)_(n)OR², —(CH₂)NR² ₂, —CO₂R²,—COR², —CONR² ₂, wherein the C₁₋₁₂ alkyl group optionally contains oneor more insertions selected from —O—, —N(R²)—, —S—, —SO—, —SO₂—; andeach substitutable nitrogen atom in Z is optionally substituted by —R³,—COR³, —SO₂R³ or —CO₂R³; wherein n is 1 to 6, preferably n is 1, 2, or3; wherein R² is hydrogen, C₁₋₁₂ alkyl, C₃₋₁₆ carbocyclyl or C₃₋₁₂heterocyclyl, C₁₋₁₂ alkylC₃₋₁₆ carbocyclyl, or C₁₋₁₂ alkylC₃₋₁₂heterocyclyl optionally substituted by one or more of C₁₋₆ alkyl,halogen, C₁₋₆ haloalkyl, —OR⁴, —SR⁴, —NO₂, CN, —NR⁴R⁴, —NR⁴COR⁴,—NR⁴CONR⁴R⁴, —NR⁴CO₂R⁴, —CO₂R⁴, —COR⁴, —CONR⁴ ₂, —SO₂R⁴, —SONR⁴ ₂,—SOR⁴, —SO₂NR⁴R⁴, —NR⁴SO₂R⁴, wherein the C₁₋₁₂ alkyl group optionallyincorporates on or two insertions selected for the group consisting of—O—, —N(R⁴)—, —S—, —SO—, —SO₂—, wherein each R⁴ may be the same ordifferent and is defined below; wherein two R² and NR² ₂ may form apartially saturated, unsaturated or fully saturated five to sevenmembered ring containing one to three heteroatoms, optionally andindependently substituted with one or more halogen, C₁₋₁₂ alkyl, C₂₋₁₂alkenyl, C₂₋₁₂ alkynyl, C₁₋₁₂ haloalkyl, C₃₋₁₂ carbocyclyl, C₃₋₁₂heterocyclyl, —OR⁵, —SR⁵, —NO₂, CN, —NR⁵R⁵, —NR⁵COR⁵, —NR⁵CONR⁵R⁵,—NR⁵CO₂R⁵, —CO₂R⁵, —COR⁵, —CONR⁵ ₂, —SO₂R⁵, —SONR⁵ ₂, —SOR⁵, —SO₂NR⁵R⁵,—NR⁵SO₂R⁵; and each saturated carbon in the optional ring is furtheroptionally and independently substituted by ═O, ═S, NNR⁶ ₂, ═N—OR⁶,═NNR⁶COR⁶, ═NNR⁶CO₂R⁶, ═NNSO₂R⁶, or ═NR⁶; wherein R³ is hydrogen, C₁₋₆alkyl, C₁₋₆ haloalkyl, or C₆₋₁₂ aryl; wherein R⁴ is hydrogen, C₁₋₆alkyl, C₁₋₆ haloalkyl, or C₆₋₁₂ aryl; wherein R⁵ is hydrogen, C₁₋₁₂alkyl, C₃₋₁₆ carbocyclyl or C₃₋₁₂ heterocyclyl, optionally substitutedby one or more of C₁₋₆ alkyl, halogen, C₁₋₆ haloalkyl, —OR⁷, —SR⁷, —NO₂,CN, —NR⁷R⁷, —NR⁷COR⁷, —NR⁷CONR⁷R⁷, —NR⁷CO₂R⁷, —CO₂R⁷, —COR⁷, —CONR⁷ ₂,—SO₂R⁷, —SONR⁷ ₂, —SOR⁷, —SO₂NR⁷R⁷, —NR⁷SO₂R⁷; wherein the C₁₋₁₂ alkylgroup optionally incorporates one or two insertions selected from thegroup consisting of —O—, —N(R⁷)—, —S—, —SO—, —SO₂—, wherein each R⁷ maybe the same or different and is defined below; wherein R⁶ is hydrogen,C₁₋₁₂ alkyl, C₃₋₁₆ carbocyclyl or C₃₋₁₂ heterocyclyl, optionallysubstituted by one or more of C₁₋₆ alkyl, halogen, C₁₋₆ haloalkyl, —OR⁷,—SR⁷, —NO₂, CN, —NR⁷R⁷, —NR⁷COR⁷, —NR⁷CONR⁷R⁷, —NR⁷CO₂R⁷, —CO₂R⁷, —COR⁷,—CONR⁷ ₂, —SO₂R⁷, —SONR⁷ ₂, —SOR⁷, —SO₂NR⁷R⁷, —NR⁷SO₂R⁷; wherein theC₁₋₁₂ alkyl group optionally incorporates one or two insertions selectedfrom the group consisting of —O—, —N(R⁷)—, —S—, —SO—, —SO₂—, whereineach R⁷ may be the same or different and is defined below; wherein R⁷ ishydrogen, C₁₋₆ alkyl, or C₁₋₆ haloalkyl; wherein the optionallysubstituted carbocyclyl or heterocyclyl group in R¹ and Z is optionallyand independently fused to a partially saturated, unsaturated or fullysaturated five to seven membered ring containing zero to threeheteroatoms, and each substitutable carbon atom in R¹ or Z, includingthe optional fused ring, is optionally and independently substituted byone or more of halogen, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₁₋₁₂haloalkyl, C₃₋₁₂ carbocyclyl, C₃₋₁₂ heterocyclyl, —(CH₂)_(n)OR¹²,—(CH₂)_(n)NR¹² ₂, —OR², —SR¹², —NO₂, CN, —NR¹²R¹², —NR¹²COR¹²,—NR¹²CONR¹²R¹², —NR¹²CO₂R¹², —CO₂R¹², —COR¹², —CONR¹² ₂, —SO₂R¹²,—SONR¹² ₂, —SOR¹², —SO₂NR¹²R¹², —NR¹²SO₂R¹²; wherein the C₁₋₁₂ alkylgroup optionally contains one or more insertions selected from —O—,—N(R¹²)—, —S—, —SO—, —SO₂—, and each saturated carbon in the optionallyfused ring is further optionally and independently substituted by ═O,═S, NNR¹³ ₂, ═N—OR¹³, ═NNR¹³COR¹³, ═NNR¹³CO₂R¹³, ═NNSO₂R¹³, or ═NR¹³;and each substitutable nitrogen atom in R¹ is optionally substituted by—R¹⁴, —COR¹⁴, —SO₂R¹⁴, or —CO₂R⁴; wherein n is 1 to 6, preferably n is1, 2, or 3; wherein R¹² is hydrogen, C₁₋₁₂ alkyl, C₃₋₁₆ carbocyclyl orC₃₋₁₂ heterocyclyl, optionally substituted by one or more of C₁₋₆ alkyl,halogen, C₁₋₆ haloalkyl, —OR¹⁵, —SR¹⁵, —NO₂, CN, —NR¹⁵R¹⁵, —NR¹⁵COR¹⁵,—NR¹⁵CONR¹⁵R¹⁵, —NR¹⁵CO₂R¹⁵, —CO₂R¹⁵, —COR¹⁵, —CONR¹⁵ ₂, —SO₂R¹⁵,—SONR¹⁵ ₂, —SOR¹⁵, —SO₂NR¹⁵R¹⁵, —NR¹⁵SO₂R¹⁵; wherein the C₁₋₁₂ alkylgroup optionally incorporates one or two insertions selected from thegroup consisting of —O—, —N(R¹⁵)—, —S—, —SO—, —SO₂—, wherein each R⁷ maybe the same or different and is defined below; wherein two R¹² and NR¹²₂ may form a partially saturated, unsaturated or fully saturated five toseven membered ring containing one to three heteroatoms, optionally andindependently substituted with one or more halogen, C₁₋₁₂ alkyl, C₂₋₁₂alkenyl, C₂₋₁₂ alkynyl, C₁₋₁₂ haloalkyl, C₃₋₁₂ carbocyclyl, C₃₋₁₂heterocyclyl, —OR¹⁶, —SR¹⁶, —NO₂, CN, —NR¹⁶R¹⁶, —NR¹⁶COR¹⁶,—NR¹⁶CONR¹⁶R¹⁶, —NR¹⁶CO₂R¹⁶, —CO₂R¹⁶, —COR¹⁶, —CONR¹⁶ ₂, —SO₂R¹⁶,—SONR¹⁶ ₂, —SOR¹⁶, —SO₂NR¹⁶R¹⁶, —NR¹⁶SO₂R¹⁶; and each saturated carbonin the optional ring is further optionally and independently substitutedby ═O, ═S, NNR¹⁷ ₂, ═N—OR¹⁷, ═NNR¹⁷COR¹⁷, ═NNR¹⁷CO₂R¹⁷, ═NNSO₂R¹⁷, or═NR¹⁷; wherein R¹³ is hydrogen, C₁₋₁₂ alkyl, C₃₋₁₆ carbocyclyl or C₃₋₁₂heterocyclyl, optionally substituted by one or more of C₁₋₆ alkyl,halogen, C₁₋₆ haloalkyl, —OR¹⁵, —SR¹⁵, —NO₂, CN, —NR¹⁵R¹⁵, —NR¹⁵COR¹⁵,—NR¹⁵CONR¹⁵R¹⁵, —NR¹⁵CO₂R¹⁵, —CO₂R¹⁵, —COR¹⁵, —CONR¹⁵ ₂, —SO₂R¹⁵,—SONR¹⁵ ₂, —SOR¹⁵, —SO₂NR¹⁵R¹⁵, —NR¹⁵SO₂R¹⁵; wherein the C₁₋₁₂ alkylgroup optionally incorporates one or two insertions selected from thegroup consisting of —O—, —N(R¹⁵)—, —S—, —SO—, —SO₂—, wherein each R¹⁵may be the same or different and is defined below; wherein R¹⁴ ishydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, or C₆₋₁₂ aryl; wherein R¹⁵ ishydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl; wherein R¹⁶ is hydrogen, C₁₋₁₂alkyl, C₃₋₁₆ carbocyclyl or C₃₋₁₂ heterocyclyl, optionally substitutedby one or more of C₁₋₆ alkyl, halogen, C₁₋₆ haloalkyl, —OR¹⁸, —SR¹⁸,—NO₂, CN, —NR¹⁸R¹⁸, —NR¹⁸COR¹⁸, —NR¹⁸CONR¹⁸R¹⁸, —NR¹⁸CO₂R¹⁸, —CO₂R¹⁸,—COR⁸, —CONR¹⁸ ₂, —SO₂R¹⁸, —SONR¹⁸ ₂, —SOR¹⁸, —SO₂NR¹⁸R¹⁸, —NR¹⁸SO₂R¹⁸;wherein the C₁₋₁₂ alkyl group optionally incorporates one or twoinsertions selected from the group consisting of —O—, —N(R¹⁸)—, —S—,—SO—, —SO₂—, wherein each R¹⁸ may be the same or different and isdefined below; wherein R¹⁷ is hydrogen, C₁₋₁₂ alkyl, C₃₋₁₆ carbocyclylor C₃₋₁₂ heterocyclyl, optionally substituted by one or more of C₁₋₆alkyl, halogen, C₁₋₆ haloalkyl, —OR¹⁸, —SR¹⁸, —NO₂, CN, —NR¹⁸R¹⁸,—NR¹⁸COR¹⁸, —NR¹⁸CONR¹⁸R¹⁸, —NR¹⁸CO₂R¹⁸, —CO₂R¹⁸, —COR¹⁸, —CONR¹⁸ ₂,—SO₂R¹⁸, —SONR¹⁸ ₂, —SOR¹⁸, —SO₂NR¹⁸R¹⁸, —NR¹⁸SO₂R¹⁸; wherein the C₁₋₁₂alkyl group optionally incorporates one or two insertions selected fromthe group consisting of —O—, —N(R¹⁸)—, —S—, —SO—, —SO₂—, wherein eachR¹⁸ may be the same or different and is defined below; wherein R¹⁸ ishydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl; that inhibits the activity of JNK2in the subject. In further embodiments, the compound has a minimaleffect on the enzymatic activity of JNK1.

In another embodiment, the invention is a method of treating type Idiabetes in a subject, comprising administering a compound of thefollowing formula:

wherein ring A is an optionally substituted benzene ring, X is —O—, —N═,—NR³— or —CHR³—, R² is an acyl group, an optionally esterified orthioesterified carboxyl group, and optionally substituted carbamoylgroup or an optionally substituted amino group and the line, a brokenline shows a single bond or a double bond, and R¹ is a hydrogen atom,optionally substituted hydrocarbon group, and optionally substitutedheterocyclic group and the like; that inhibits the activity of JNK2 inthe subject. In further embodiments, the compound has a minimal effecton the enzymatic activity of JNK1.

In another embodiment, the invention is a method of treating type Idiabetes in a subject, comprising administering a compound of thefollowing formula:

wherein each of Ar^(a) and Ar^(b) is an aromatic group optionally havingsubstituents, Ar^(a) and Ar^(b) optionally form a condensed cyclic grouptogether with the adjacent carbon atom; ring B^(a) is anitrogen-containing heterocycle optionally having substituents; X^(a)and Y^(a) are the same or different and each is (1) a bond, (2) anoxygen atom, (3) S(O)_(p) (wherein p is an integer of 0 to 2), (4)NR^(d) (wherein R^(d) is a hydrogen atom or a lower alkyl group) or (5)a divalent linear lower hydrocarbon group optionally having substituentsand containing 1 to 3 hetero atom(s); ring A^(a) is a 5-membered ringoptionally having substituents; R^(a) and R^(b) are the same ordifferent and each is (1) a hydrogen atom, (2) a halogen atom, (3) ahydrocarbon group optionally having substituents, (4) an acyl group or(5) a hydroxy group optionally having a substituent; R_(c) is (1) ahydrogen atom, (2) a hydroxy group optionally substituted by a loweralkyl group or (3) a carboxyl group; that inhibits the activity of JNK2in the subject. In further embodiments, the compound has a minimaleffect on the enzymatic activity of JNK1.

In another embodiment, the invention is a method of treating type Idiabetes in a subject, comprising administering a compound of thefollowing formula:

that inhibits the activity of JNK2 in the subject. In furtherembodiments, the compound has a minimal effect on the enzymatic activityof JNK1.

In another embodiment, the invention is a method of treating type Idiabetes in a subject, comprising administering a compound of thefollowing formula:

wherein Y is selected from O, NH, N(R), S, S(O) or S(O)₂; X is selectedfrom O, NH or N(R); R¹ and R² are each independently selected from H, aC₁-C₆ straight chain or branched alkyl or alkenyl group, optionallysubstituted with one to four substituents, each of which isindependently selected from NH₂, NHR, N(R)₂, NO₂, OH, OR, CF₃, halo, CN,CO₂H, CONH₂, CONHR, CON(R)₂, COR, SR, S(O)R, S(O)₂R, S(O)2NH₂, S(O)₂NHRor R; a 5-7 membered aromatic or non-aromatic carbocyclic orheterocyclic ring, optionally substituted with one to four substituents,each of which is independently selected from NH₂, NHR, N(R)₂, NO₂, OH,OR, CF₃, halo, CN, CO₂H, CONH₂, CONHR, CON(R)₂, COR, SR, S(O)R, S(O)₂R,S(O)₂NH₂, S(O)₂NHR or R; or a 9-10 membered bicyclic aromatic ornon-aromatic carbocyclic or heterocyclic ring optionally substitutedwith one to four substituents, each of which is independently selectedfrom NH₂, NHR, N(R)₂, NO₂, OH, OR, CF₃, halo, CN, CO₂H, CONH₂, CONHR,CON(R)₂, COR, SR, S(O)R, S(O)₂R, S(O)₂NH₂, S(O)₂NHR or R; wherein saidheterocyclic ring contains 1 to 4 heteroatoms, each of which heteroatomsare independently selected from N, O, S, SO or SO₂; and R is selectedfrom a C₁-C₆ straight chain or branched alkyl or alkenyl group, a 5-7membered aromatic or non-aromatic carbocyclic or heterocyclic ring, or a9-10 membered bicyclic aromatic or non-aromatic carbocyclic orheterocyclic ring system; that inhibits the activity of JNK2 in thesubject. In further embodiments, the compound has a minimal effect onthe enzymatic activity of JNK1.

In another embodiment, the invention is a method of treating type Idiabetes in a subject, comprising administering a compound of thefollowing formula:

wherein ring A and ring B are each an optionally substituted benzenering, X is —O—, —N═, —NR³— or —CHR³—, R² is an acyl group, an optionallyesterified or thioesterified carboxyl group, and optionally substitutedcarbamoyl group or an optionally substituted amino group and the line, abroken line shows a single bond or a double bond, and R¹ is a hydrogenatom, optionally substituted hydrocarbon group, and optionallysubstituted heterocyclic group and the like; that inhibits the activityof JNK2 in the subject. In further embodiments, the compound has aminimal effect on the enzymatic activity of JNK1.

In another embodiment, the invention is a method of treating type Idiabetes in a subject, comprising administering a compound of thefollowing formula:

wherein X is O, S or NR⁰, with R⁰ being H or an unsubstituted orsubstituted C₁-C₆ alkyl; G is an unsubstituted or substitutedpyrimidinyl group; R¹ is selected from the group comprising orconsisting of hydrogen, unsubstituted or substituted C₁-C₆-alkoxy,unsubstituted or substituted C₁-C₆-thioalkoxy, unsubstituted orsubstituted C₁-C₆-alkyl, unsubstituted or substituted C₂-C₆-alkenylunsubstituted or substituted C₂-C₆-alkynyl, primary, secondary ortertiary amino groups, aminoacyl, aminocarbonyl, unsubstituted orsubstituted C₁-C₆ alkoxycarbonyl unsubstituted or substituted aryl,unsubstituted or substituted heteroaryl, carboxyl, cyano, halogen,hydroxy, nitro, sulfoxy, sulfonyl sulfonamide, unsubstituted orsubstituted hydrazides; R² is selected from the group comprising orconsisting of hydrogen, unsubstituted or substituted C₁-C₆-alkyl,unsubstituted or substituted C₂-C₆-alkenyl, unsubstituted or substitutedC₂-C₆-alkynyl, unsubstituted or substituted C₁-C₆-alkyl-aryl,unsubstituted or substituted aryl or heteroaryl unsubstituted orsubstituted C₁-C₆-alkyl-heteroaryl, —C(O)—OR³, —C(O)—R³,—C(O)—NR³R^(3′), —(SO₂)R³, with R³ and R^(3′) being independentlyselected from the group comprising or consisting of hydrogen,unsubstituted or substituted C₁-C₆ alkyl, unsubstituted or substitutedC₂-C₆ alkenyl, unsubstituted or substituted C₂-C₆ alknyl, unsubstitutedor substituted aryl, unsubstituted or substituted heteroaryl,unsubstituted or substituted C₁-C₆-alkyl aryl, unsubstituted orsubstituted C₁-C₆-alkyl heteroaryl; that inhibits the activity of JNK2in the subject. In further embodiments; the compound has a minimaleffect on the enzymatic activity of JNK1.

In another embodiment, the invention is a method of treating type Idiabetes in a subject, comprising administering a compound of thefollowing formula:

wherein Y is selected from —(CH₂)-Q¹; —(CO)-Q¹; —(CO)NH-Q¹; —(CO)—O-Q¹;—(SO₂)-Q¹ or —(SO₂)NH-Q¹; Q¹ is a C₁-C₆ straight chain or branched alkylor alkenyl group; a 5-7 membered aromatic or non-aromatic carbocyclic orheterocyclic ring; or a 9-14 membered bicyclic or tricyclic aromatic ornon-aromatic carbocyclic or heterocyclic ring system, wherein saidalkyl, alkenyl, ring or ring system is optionally substituted with oneto four substituents, each of which is independently selected from NH₂,NH—R, N(R)₂, NO₂, OH, OR, CF₃, halo, CN, CO₂H, C(O)—NH₂, C(O)—NH—R,C(O)—N(R)₂, C(O)—R, SR, S(O)—R, S(O)₂—R, S(O)₂—NH—R or —R; W is N or C;wherein when W is N, R⁸ is a lone pair of electrons; and wherein when Wis C, R⁸ is R⁷. A¹ is N or CR¹; A² is N or CR²; A³ is N or CR³; A⁴ is Nor CR⁴; provided that at least one of A¹, A², A³ and A⁴ must not be N;R¹ is —NHR⁵, —OR⁵, —SR⁵, or —R⁵; R², R³, and R⁴ are independentlyselected from —(CO)NH₂, —(CO)NHR, —(CO)N(R)₂, —NHR⁵, —NHCH₂R⁵, —OR⁵,—SR⁵, —R⁵, —NH(CO)—R⁶, —NH(CO)—NHR⁶, —NH(CO)—NH(CO)R⁶, —NH(CO)—OR⁶,—NH(SO₂)—R⁶, —NH(SO₂)—NHR⁶, —C(O)OH, —C(O)OR, —(CO)-Q¹, —(CO)NH-Q¹,—(CO)NR-Q¹, —(CO)—O-Q¹, —(SO₂)-Q¹ or —(SO₂)NH-Q¹; R⁵ and R⁶ are eachindependently selected from H; N(R)₂, NHOH, NO₂, C(O)OR or halo; a C₁-C₆straight chain or branched alkyl, alkenyl or alkynyl group; a 5-7membered aromatic or non-aromatic carbocyclic or heterocyclic ring; or a9-14 membered bicyclic or tricyclic aromatic or non-aromatic carbocyclicor heterocyclic ring; wherein said alkyl, alkenyl, ring or ring systemis optionally substituted with one to four substituents, each of whichis independently selected from NH₂, NHR, NHC(O)OR, N(R)₂, NO₂, OH, OR,CF₃, halo, CN, Si(R)₃, CO2H, COOR, CONH₂, CONHR, CON(R)₂, COR, SR,S(O)R, S(O)₂R, S(O)₂NHR or R; R⁷ is H; a C₁-C₆ straight chain orbranched alkyl or alkenyl group; a 5-7 membered aromatic or non-aromaticcarbocyclic or heterocyclic ring; or a 9-14 membered bicyclic ortricyclic aromatic or non-aromatic carbocyclic or heterocyclic ring;wherein said alkyl, alkenyl, ring or ring system is optionallysubstituted with one to four substituents, each of which isindependently selected from NH₂, NHR, N(R)₂, NO₂, OH, OR, CF₃, halo, CN,CO₂H, CONH₂, CONHR, CON(R)₂, COR, SR, S(O)R, S(O)₂R, S(O)₂NHR or R; R isa C₁-C₆ straight chain or branched alkyl or alkenyl group, a 5-7membered aromatic or non-aromatic carbocyclic or heterocyclic ring, or a9-10 membered bicyclic aromatic or non-aromatic carbocyclic orheterocyclic ring system; and Z is CH or N; that inhibits the activityof JNK2 in the subject. In further embodiments, the compound has aminimal effect on the enzymatic activity of JNK1.

In another embodiment, the invention is a method of treating type Idiabetes in a subject, comprising administering a compound of thefollowing formula:

wherein: R¹ is aryl or heteroaryl, each of which is optionallysubstituted with one or more of R³, OR³, OCOR³, COOR³, COR³, CON⁴R³R⁴,NHCOR³, NR³R⁴, NHSO₂R³, SO₂R³, SO₂NR³R⁴, SR³, CN, halogen, and NO₂; R²is R⁵, R⁶, COR^(s), COR^(S), CONHR⁵, CONHR⁶, CON(R⁶)₂, COOR⁵, COOR⁶,SO₂R⁵ or SO₂R⁶; R3 and R4 are each independently hydrogen, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, (C₃₋₈ cycloalkyl) C₁₋₄alkyl, heterocycle, heterocycle C₁₋₆ alkyl, C₁₋₆ fluoroalkyl, C₁₋₆trifluoroalkoxy; R⁵ is aryl or heteroaryl, each of which is optionallysubstituted with one or more of R⁷, OR⁷, OCOR⁷, COOR⁷, COR⁷, CONR⁷R⁸,CONHOR⁷, NHCOR⁷, NR⁷R⁸, NHSO₂R⁷, SO₂R⁷, SO₂NHR⁷R⁸, SR⁷, R⁷SR⁸, CN,halogen, oxygen and NO₂; R⁶ is hydrogen, C₄₋₆ alkyl, C₃₋₈ cycloalkyl,(C₃₋₈ cycloalkyl) C₁₋₆ alkyl, heterocycle, heterocycle C₁₋₆ alkyl,heteroaryl C₁₋₆ alkyl, aryl C₁₋₆ alkyl, C₁₋₆ alkoxy, or C₂₋₆ alkenyl,wherein any of C₁₋₆ alkyl, C₃₋₈ cycloalkyl, (C₃₋₈ cycloalkyl) C₁₋₆alkyl, heterocycle, heterocycle C₁₋₆ alkyl, heteroaryl C₁₋₆ alkyl, arylC₁₋₆ alkyl, C₁₋₆ alkoxy and C₂₋₆ alkenyl is optionally substituted withone or more A; R⁷ and R⁸ are each independently hydrogen, C₁₋₆ alkyl,C₃₋₈ cycloalkyl, (C₃₋₈ cycloalkyl) C₁₋₆ alkyl, C₂₋₆ alkenyl, aryl,heteroaryl, heteroaryl C₁₋₆ alkyl, heterocycle, heterocycle C₁₋₆ alkyl,aryl, C₁₋₆ fluoroalkyl and C₁₋₆ chloroalkyl, wherein any of C₁₋₆ alkyl,C₃₋₈ cycloalkyl, (C₃₋₈ cycloalkyl) C₁₋₆ alkyl, C₂₋₆ alkenyl, heteroaryl,heteroaryl C₁₋₆ alkyl, heterocycle and heterocycle C₁₋₆ alkyl isoptionally substituted with one or more B; R⁹ and R¹⁰ are eachindependently hydrogen, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, (C₃₋₈ cycloalkyl)C₁₋₆ alkyl, C₂₋₆ alkenyl, heterocycle, heterocycle C₁₋₆ alkyl,heteroaryl, heteroaryl C₁₋₆ alkyl, aryl or aryl C₁₋₆ alkyl, wherein anyof C₁₋₆ alkyl, C₃₋₈ cycloalkyl, (C₃₋₈ cycloalkyl) C₁₋₆ alkyl, C₂₋₆alkenyl, heterocycle, heterocycle C₁₋₆ alkyl, heteroaryl, heteroarylC₁₋₆ alkyl, aryl or aryl C₁₋₆ alkyl is optionally substituted with oneor more B; A is R⁹, OR⁹, OCOR⁹, COOR⁹, COR⁹, CONR⁹R¹⁰, CONHOR⁹, NHCOR⁹,NR⁹R¹⁰, NR⁹SO₂R¹⁰, SO₂R⁹, SO₂NR⁹R¹⁰, SR⁹, R⁹SR¹⁰, CN or halogen; B isC₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino, di (C₁₋₆ alkyl)amino orhalogen; that inhibits the activity of JNK2 in the subject. In furtherembodiments, the compound has a minimal effect on the enzymatic activityof JNK1.

In another embodiment, the invention is a method of treating type Idiabetes in a subject, comprising administering a compound of thefollowing formula:

wherein: R¹ is selected from hydrogen, CONH₂, T_((n))-R, or T_((n))-Ar¹;R is an aliphatic or substituted aliphatic group; n is zero or one; T isC(═O), CO₂, CONH, S(O)₂, S(O)₂NH, COCH₂ or CH₂; R₂ is selected fromhydrogen, —R, —CH₂OR, —CH₂OH, —CH═O, —CH₂SR, —CH₂S(O)₂R, —CH₂(C═O)R,—CH₂CO₂R, —CH₂CO₂H, —CH₂CN, —CH₂NHR, —CH₂N(R)₂, —CH═N—OR, —CH═NNHR,—CH═NN(R)₂, —CH═NNHCOR, —CH═NNHCO₂R, —CH═NNHSO₂R, -aryl, —CH₂(aryl),—CH₂NH₂, —CH₂NHCOR, —CH₂NHCONHR, —CH₂NHCON(R)₂, —CH₂NRCOR, —CH₂NHCO₂R,—CH₂CONHR, —CH₂CON(R)₂, —CH₂SO₂NH₂, —CH₂(heterocyclyl), or-(heterocyclyl); R³ is selected from hydrogen, —R, hydroxyalkyl,alkoxyalkyl, alkylthioalkyl, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, oraryloxyalkyl; G is hydrogen or C₁₋₃ alkyl; Q-NH is

wherein the H of Q-NH is optionally replaced by R, COR, S(O)₂R, or CO₂R;A is N or CH; Ar¹ is aryl, substituted aryl, heterocyclyl or substitutedheterocyclyl, wherein Ar¹ is optionally fused to a partially unsaturatedor fully unsaturated five to seven membered ring containing zero tothree heteroatoms; wherein each substitutable carbon atom in Ar¹,including the fused ring when present, is optionally and independentlysubstituted by halo, R, OR, SR, OH, NO₂, CN, NH₂, NHR, N(R)₂, NHCOR,NHCONHR, NHCON(R)₂, NRCOR, NHCO₂R, CO₂R, CO₂H, COR, CONHR, CON(R)₂,S(O)₂R, SONH₂, S(O)R, SO₂NHR, or NHS(O)₂R, and wherein each saturatedcarbon in the fused ring is further optionally and independentlysubstituted by ═O, ═S, ═NNHR, ═NNR₂, ═N—OR, ═NNHCOR, ═NNHCO₂R, ═NNHSO₂R,or ═NR; and wherein each substitutable nitrogen atom in Ar¹ isoptionally substituted by R, COR, S(O)₂R, or CO₂R; that inhibits theactivity of JNK2 in the subject. In further embodiments, the compoundhas a minimal effect on the enzymatic activity of JNK1.

In another embodiment, the invention is a method of treating type Idiabetes in a subject, comprising administering a compound of thefollowing formula:

wherein: X—Y—Z is selected from one of the following:

R¹ is H, CONH₂, T_((n))-R, or T_((n)-Ar) ²; R is an aliphatic orsubstituted aliphatic group; n is zero or one; T is C(═O), CO₂, CONH,S(O)₂, S(O)₂NH, COCH₂ or CH₂; each R² is independently selected fromhydrogen, —R, —CH₂OR, —CH₂OH, —CH═O, —CH₂SR, —CH₂S(O)₂ R, —CH₂(C═O)R,—CH₂CH₂CO₂R, —CH₂CO₂H, —CH₂CN, —CH₂NHR, —CH₂N(R)₂, —H═N—OR, —CH═NNHR,—CH═NN(R)₂, —CH═NNHCOR, —CH═NNHCO₂R, —CH═NNHSO₂R, -aryl, -substitutedaryl, —CH₂(aryl), —CH₂(substituted aryl), —CH₂ NHz, —CH₂NHCOR,—CH₂NHCONHR, —CH₂NHCON(R)₂, —CH₂NRCOR, —CH₂NHCO₂R, —CH₂CONHR,—CH₂CON(R)₂, —CH₂SO₂NH₂, —CH₂ (heterocyclyl), —CH₂ (substitutedheterocyclyl), —(heterocyclyl), or —(substituted heterocyclyl); each R³is independently selected from hydrogen, R, COR, CO²R or S(O)²R; C is Ror Ar¹; Ar¹ is aryl, substituted aryl, arylalkyl, substituted arylalkyl,heterocyclyl, or substituted heterocyclyl, wherein Ar¹ is optionallyfused to a partially unsaturated or fully unsaturated five to sevenmembered ring containing zero to three heteroatoms; Q-NH is

wherein the H of Q-NH is optionally replaced by R³; Ar² is aryl,substituted aryl, heterocyclyl or substituted heterocyclyl, wherein Ar²is optionally fused to a partially unsaturated or fully unsaturated fiveto seven membered ring containing zero to three heteroatoms; whereineach substitutable carbon atom in Ar², including the fused ring whenpresent, is optionally and independently substituted by halo, R, OR, SR,OH, NO₂, CN, NH₂, NHR, N(R)₂, NHCOR, NHCONHR, NHCON(R)₂, NRCOR, NHCO₂R,CO₂R, CO₂H, COR, CONHR, CON(R)₂, S(O)R, SONH₂, S(O)R, SO₂NHR, orNHS(O)₂R, and wherein each saturated carbon in the fused ring is furtheroptionally and independently substituted by ═O, ═S, ═NNHR, ═NNR₂, ═N—OR,═NNHCOR, ═NNHCO₂R, ═NNHSO₂R, or ═NR; and wherein each substitutablenitrogen atom in Ar² is optionally substituted by R, COR, S(O)₂R, orCO₂R; that inhibits the activity of JNK2 in the subject. In furtherembodiments, the compound has a minimal effect on the enzymatic activityof JNK1.

In another embodiment, the invention is a method of treating type Idiabetes in a subject, comprising administering a compound of thefollowing formula:

wherein: A and B are each independently selected from N or CH; R¹ and R²are each independently selected from halogen, CN, NO₂, N(R)₂, OR, SR, or(T)_(n)-R⁵; R³ is selected from a 3-6 membered carbocyclic orheterocyclic ring having one to two heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, phenyl, or a 5-6 membered heteroarylring having one to three heteroatoms independently selected fromnitrogen, oxygen, or sulfur, wherein said phenyl or heteroaryl ring isoptionally substituted with one (T)_(n)-Ar and one to two R⁷; each n isindependently selected from zero or one; T is a C₁-C₆ alkylidene chain,wherein one methylene unit of T is optionally replaced by CO, CO₂, COCO,CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO₂, NRCONR, SO₂, NRSO₂, SO₂NR,NRSO₂NR, O, S, or NR; each R is independently selected from hydrogen oran optionally substituted C₁-C₆ aliphatic group; or two R on the samenitrogen atom may be taken together with the nitrogen to form a four toeight membered, saturated or unsaturated heterocyclic ring containingone to three heteroatoms independently selected from nitrogen, oxygen,or sulfur; R⁴ is (T)_(n)-R, (T)_(n)-Ar, or (T)_(n)-Ar¹; R^(a) isselected from R^(b), halogen, NO₂, OR^(b), SR^(b), or N(R^(b))₂; R^(b)is selected from hydrogen or a C₁-C₄ aliphatic group optionallysubstituted with oxo, OH, SH, NH₂, halogen, NO₂, or CN; R⁵ is anoptionally substituted C₁-C₆ aliphatic or Ar; Ar is a 5-6 memberedsaturated, partially unsaturated, or aryl monocyclic ring having zero tothree heteroatoms independently selected from nitrogen, sulfur, oroxygen, or an 8-10-membered saturated, partially unsaturated, or arylbicyclic ring having zero to four heteroatoms independently selectedfrom nitrogen, sulfur, or oxygen, wherein Ar is optionally substitutedwith one to three R⁷; Ar¹ is a 6-membered aryl ring having zero to twonitrogens, wherein said ring is substituted with one Z—R⁶ group andoptionally substituted with one to three R⁷; Z is a C₁-C₆ alkylidenechain wherein up to two nonadjacent methylene units of Z are optionallyreplaced by CO, CO₂, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO₂,NRCONR, SO, SO₂, NRSO₂, SO₂NR, NRSO₂NR, O, S, or NR; provided that saidoptionally replaced methylene unit of Z is a methylene unit non-adjacentto R⁶; R⁶ is selected from Ar, R, halogen, NO₂, CN, OR, SR, N(R)₂,NRC(O)R, NRC(O)N(R)₂, NRCO₂R, C(O)R, CO₂R, OC(O)R, C(O)N(R)₂,OC(O)N(R)₂, SOR, SO₂R, SO₂N(R)₂, NRSO₂R, NRSO₂N(R)₂, C(O)C(O)R, orC(O)CH₂C(O)R; and each R⁷ is independently selected from R, halogen,NO₂, CN, OR, SR, N(R)₂, NRC(O)R, NRC(O)N(R)₂, NRCO₂R, C(O)R, CO₂R,C(O)N(R)₂, OC(O)N(R)₂, SOR, SO₂R, SO₂N(R)₂, NRSO₂R, NRSO₂N(R)₂,C(O)C(O)R, or C(O)CH₂C(O)R; or two R⁷ on adjacent positions of Ar¹ maybe taken together to form a saturated, partially unsaturated, or fullyunsaturated five to seven membered ring containing zero to threeheteroatoms selected from O, S, or N; that inhibits the activity of JNK2in the subject. In further embodiments, the compound has a minimaleffect on the enzymatic activity of JNK1.

In another embodiment, the invention is a method of treating type Idiabetes in a subject, comprising administering a compound of thefollowing formula:

wherein: each W is independently selected from nitrogen or CH; each R¹,R², and R³ is independently selected from halogen, QR, Q_((n))CN,Q_((n))NO₂, or Q_((n))Ar; wherein: R¹ and R² or R² and R³ are optionallytaken together to form a 4-8 membered saturated, partially unsaturated,or fully unsaturated ring having 0-3 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur; n is zero or one; Q is a C₁₋₄alkylidene chain wherein one methylene unit of Q is optionally replacedby O, S, NR, NRCO, NRCONR, NRCO₂, CO, CO₂, CONR, OC(O)NR, SO₂, SO₂NR,NRSO₂, NRSO₂NR, C(O)C(O), or C(O)CH₂C(O); each R is independentlyselected from hydrogen or an optionally substituted C₁-C₄ aliphatic,wherein: two R bound to the same nitrogen atom are optionally takentogether with the nitrogen atom to form a 3-7 membered saturated,partially unsaturated, or fully unsaturated ring having 1-2 additionalheteroatoms independently selected from nitrogen, oxygen, or sulfur; R⁴is Ar¹, T-Ar², or T_((n))-Ar³; T is a C₁₋₂ alkylidene chain wherein onemethylene unit of T is optionally replaced by O, NR, NRCO, NRCONR,NRCO₂, CO, CO2, CONR, OC(O)NR, SO₂, SO₂NR, NRSO₂, NRSO₂NR, C(O)C(O), orC(O)CH₂C(O); Ar¹ is a 5-6 membered monocyclic or 8-10 membered bicyclicsaturated, partially unsaturated, or fully unsaturated ring system;wherein: Ar1 is optionally substituted with up to five substituents,wherein the first substituent is selected from R^(x) or R⁵ and whereinany additional substituents are independently selected from R⁵; eachR^(x) is independently selected from a 5-6 membered aryl ring having 0-3heteroatoms selected from nitrogen, oxygen, or sulfur, wherein: R^(x) isoptionally substituted with 1-3 R⁵; each R⁵ is independently selectedfrom R, halogen, NO₂, CN, OR, SR, N(R)₂, NRC(O)R, NRC(O)N(R)₂, NRCO₂R,C(O)R, CO₂R, C(O)N(R)₂, OC(O)N(R)₂, SOR, SO₂R, SO₂N(R)₂, NRSO₂R,NRSO₂N(R)₂, C(O)C(O)R, or C(O)CH₂C(O)R; Ar² is a 5-6 membered saturated,partially unsaturated, or fully unsaturated monocyclic ring having 0-3heteroatoms independently selected from nitrogen, oxygen, or sulfur, oran 8-10 membered saturated, partially unsaturated, or fully unsaturatedbicyclic ring system having 0-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur; wherein: Ar² is optionally substituted withup to five substituents, wherein the first substituent is selected fromR^(x) or R⁵ and wherein any additional substituents are independentlyselected from R⁵; Ar³ is a 6-membered aryl ring having 0-2 nitrogens,wherein: Ar³ is substituted with one Z—R group and optionallysubstituted with 1-3 R⁵; Z is a C₁-C₆ alkylidene chain wherein up to twonon adjacent methylene units of Z are optionally replaced by CO, CO₂,COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO₂, NRCONR, SO, SO₂, NRSO₂,SO₂NR, NRSO₂NR, O, S, or NR; and R⁶ is selected from Ar², R, halogen,NO₂, CN, OR, SR, N(R)₂, NRC(O)R, NRC(O)N(R)₂, NRCO₂R, C(O)R, CO₂R,OC(O)R, C(O)N(R)₂, OC(O)N(R)₂, SOR, SO₂R, SO₂N(R)₂, NRSO₂R, NRSO₂N(R)₂,C(O)C(O)R, or C(O)CH₂C(O)R; that inhibits the activity of JNK2 in thesubject. In further embodiments, the compound has a minimal effect onthe enzymatic activity of JNK1.

In another embodiment, the invention is a method of treating type Idiabetes in a subject, comprising administering a compound of thefollowing formula:

wherein R¹ is —F, —Cl, —Br, —OH, —SH, —NH₂, or —CH₃; R² is —F, —Cl, —Br—OH, —SH, —NH₂, or —CH₃; R³ is —H, —F, —Cl, —Br, —OH, —SH, —NH₂, —CH₃,—OCH₃, or —CH₂CH₃; R⁴ is —C₁₋₄ alkyl optionally substituted with a —C₃₋₇cycloalkyl; R⁵ is —C₁₋₄ alkyl or —C₃₋₇ cycloalkyl, wherein the —C₁₋₄alkyl is optionally substituted with a phenyl; X is a bond or an alkylbridge having 1-3 carbons; Y is —NH— or —NH₂+—; and HETCy is a 4 to 10membered non-aromatic heterocycle containing at least one N atom,optionally containing 1-2 additional N atoms and 0-10 or S atom, andoptionally substituted with —C₁₋₄ alkyl or —C(O)—O—CH₂-phenyl; thatinhibits the activity of JNK2 in the subject. In further embodiments,the compound has a minimal effect on the enzymatic activity of JNK1.

DESCRIPTION OF THE FIGURES

FIG. 1. Spontaneous diabetes is decreased in JNK2-deficient mice. Thepresence of hyperglycemia (blood glucose>200 mg/dl) was examined in acohort of 32 NOD mice and 28 female NOD/Mapk9−/− mice. The data arepresented as the % of mice with hyperglycemia.

FIG. 2A. JNK2-defiency causes reduced insulitis in NOD mice.Representative islets from 13-week-old mice stained with hematoxylin andeosin are shown.

FIG. 2B. The extent of insulitis was quantitated (6 mice per genotype;10 to 20 islets per mouse). The percentage of islets with normalmorphology and with inflammatory infiltration that was restricted to theperiphery of the islet (peri-insulitis) or throughout the islet(insulitis) is shown. 0=normal islet, 1=peri-insulitis, 2=insulitis.

FIG. 3A. JNK2-deficiency causes reduced diabetes in adoptive transferstudies. Splenocytes isolated from pre-diabetic 13 week old NOD orNOD/Mapk9−/− mice were adoptively transferred to immune-deficientNOD/Scid mice. The incidence of diabetes was monitoredpost-transplantation.

FIG. 3B. Splenocytes isolated from diabetic NOD mice were adoptivelytransferred irradiated NOD or NOD/Mapk9−/− male mice. The incidence ofdiabetes was monitored post-transplantation.

FIG. 4A. T cell defects in JNK2-deficient NOD mice. Pancreatic sectionsof NOD and NOD/Mapk9−/− mice were stained with either anti-CD4 oranti-CD8 antibodies (green) and counterstained with DAPI (blue). Stainedsections of representative infiltrated islets are illustrated.

FIG. 4B. CD4+ T cells isolated from 8-week-old female mice weredifferentiated in the absence (Th0) or the presence of exogenously addedpolarizing cytokine to Th1 (IL-12) or Th2 (IL-4) effector cells for 4days. The cells were washed prior to re-stimulation with an immobilizedantibody to CD3 for 24 h. Cytokine secretion into the culturesupernatant was measured by ELISA. The data presented are the mean±SD oftriplicate determinations.

FIG. 4C. Cytokine amounts in the medium of Th0 cultures afterdifferentiation for 4 days and prior to washing and re-stimulation. Thedata presented are the mean±SD of triplicate determinations.

DEFINITIONS

“Acylamino” or “aminoacyl” refers to a group —NR(CO)R′ where each R, R′is independently hydrogen or “C₁-C₆-alkyl” or “aryl” or “heteroaryl” or“aryl C₁-C₆-alkyl” or “heteroaryl C₁-C₆-alkyl”.

“Acyloxy” means an —OC(O)alkyl group.

“Adverse drug reaction” means any response to a drug that is noxious andunintended and occurs in doses for prophylaxis, diagnosis, or therapyincluding side effects, toxicity, hypersensitivity, drug interactions,complications, or other idiosyncrasy. Side effects are often adversesymptom produced by a therapeutic serum level of drug produced by itspharmacological effect on unintended organ systems (e.g., blurred visionfrom anticholinergic antihistamine). A toxic side effect is an adversesymptom or other effect produced by an excessive or prolonged chemicalexposure to a drug (e.g., digitalis toxicity, liver toxicity).Hypersensitivities are immune-mediated adverse reactions (e.g.,anaphylaxis, allergy). Drug interactions are adverse effects arisingfrom interactions with other drugs, foods or disease states (e.g.,warfarin and erythromycin, cisapride and grapefruit, loperamide andClostridium difficile colitis). Complications are diseases caused by adrug (e.g., NSAID-induced gastric ulcer, estrogen-induced thrombosis).The adverse drug reaction may be mediated by known or unknown mechanisms(e.g., Agranulocytosis associated with chloramphenicol or clozapine).Such adverse drug reaction can be determined by an subject observation,assay or animal model well-known in the art.

“Alkyl” means a straight chain or branched, saturated or unsaturatedalkyl, cyclic or non-cyclic hydrocarbon having from 1 to 10 carbonatoms. Representative saturated straight chain alkyls include methyl,ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, and the like; whilesaturated branched alkyls include isopropyl, sec-butyl, isobutyl,tert-butyl, isopentyl, and the like. Unsaturated alkyls contain at leastone double or triple bond between adjacent carbon atoms (also referredto as an “alkenyl” or “alkynyl”, respectively). Representative straightchain and branched alkenyls include ethylenyl, propylenyl, 1-butenyl,2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl,2-methyl-2-butenyl, 2,3-dimethyl-2-butynyl and the like; whilerepresentative straight chain and branched alkynyls include acetylenyl,propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl,3-methyl-1-butynyl, and the like. Representative saturated cyclic alkylsinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like;while unsaturated cyclic alkyls include cyclopentenyl and cyclohexenyl,and the like. Cycloalkyls are also referred to herein as “carbocyclic”rings systems, and include bi- and tri-cyclic ring systems having from 8to 14 carbon atoms such as a cycloalkyl (such as cyclopentane orcyclohexane) fused to one or more aromatic (such as phenyl) ornon-aromatic (such as cyclohexane) carbocyclic rings.

“Alkylamino” means —NH(alkyl).

An “alkenyl group” or “alkylene group” means a monovalent unbranched orbranched hydrocarbon chain having one or more double bonds therein. Thedouble bond of an alkenyl group can be unconjugated or conjugated toanother unsaturated group. Suitable alkenyl groups include, but are notlimited to, (C₂-C₆) alkenyl groups, such as vinyl, allyl, butenyl,pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl,2-propyl-2-butenyl, 4-(2-methyl-3-butene)-pentenyl. An alkenyl group canbe unsubstituted or substituted.

“Alkylidene” means the divalent radical —C_(n)H_(2n)—, wherein n is aninteger from 1 to 8, such as —CH₂—, —CH₂CH₂—, —CH₂—CH₂—CH₂—,—CH₂CH₂CH₂CH₂—, and the like, unsubstituted or substituted with one ormore alkyl groups.

“Alkoxy” refers to a group —O—R where R includes “C₁-C₆-alyl” or “aryl”or “hetero-aryl” or “aryl C₁-C₆-alkyl” or “heteroaryl C₁-C₆-alkyl”.Preferred alkoxy groups include by way of example, methoxy, ethoxy,phenoxy and the like.

“Alkoxycarbonyl” refers to a group —C(O)OR where R includes H,“C₁-C₆-alkyl” or “aryl” or “heteroaryl” or “aryl C₁-C₆-alkyl” or“heteroaryl C₁-C₆-alkyl”.

“Alkynyl” refers to alkynyl groups preferably having from 2 to 6 carbonatoms and having at least 1-2 sites of alkynyl unsaturation. Examplesinclude ethynyl (—C≡CH), propargyl (—CH₂C≡CH), and the like.

“Aminoalkyl” means -(alkyl)-NH₂.

“Aminoalkoxy” means —O-(alkyl)-NH₂.

“Aminocarbonyl” and the like refers to a group —C(O)NRR′ where each R,R′ is independently hydrogen or “C₁-C₆-alkyl” or “aryl” or “heteroaryl”or “aryl C₁-C₆-alkyl” or “heteroaryl C₁-C₆-alkyl”.

“Aryl” means a carbocyclic or heterocyclic aromatic group containingfrom 5 to 10 ring atoms. The ring atoms of a carbocyclic aromatic groupare all carbon atoms, and include, but are not limited to, phenyl,tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as wellas benzo-fused carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl.A carbocyclic aromatic group can be unsubstituted or substituted.Preferably, the carbocyclic aromatic group is a phenyl group. The ringatoms of a heterocyclic aromatic group contains at least one heteroatom,preferably 1 to 3 heteroatoms, independently selected from nitrogen,oxygen, and sulfur. Illustrative examples of heterocyclic aromaticgroups include, but are not limited to, pyridinyl, pyridazinyl,pyrimidyl, pyrazyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl,(1,2,3,)- and (1,2,4)-triazolyl, pyrazinyl, pyrimidinyl, tetrazolyl,furyl, thienyl, isoxazolyl, thiazolyl, furyl, phenyl, isoxazolyl,indolyl, oxetanyl, azepinyl, piperazinyl, morpholinyl, dioxanyl,thietanyl and oxazolyl. A heterocyclic aromatic group can beunsubstituted or substituted. Preferably, a heterocyclic aromatic is amonocyclic ring, wherein the ring comprises 2 to 5 carbon atoms and 1 to3 heteroatoms.

“Arylamino” means —NH(aryl).

“Arylalkylamino” means —NH-(alkyl)-(aryl), wherein alkyl and aryl aredefined above. Preferably, arylalkylamino is —NH-benzyl or—NHCH₂-pyridinyl.

“Aryloxy” means —O-aryl group, wherein aryl is as defined above. Anaryloxy group can be unsubstituted or substituted. Preferably, the arylring of an aryloxy group is a phenyl group “Aryl C₁-C₆-alkyl” or“Arylalkyl” and the like, refers to C₁-C₆-alkyl groups, as definedabove, having an aryl substituent, including benzyl, phenethyl and thelike.

“C₁-C₆-alkyl” or “C₁₋₆-alkyl” and the like refer to monovalent branchedor unbranched alkyl groups having 1 to 6 carbon atoms. This term isexemplified by groups such as methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, tert-butyl, n-hexyl and the like.

“C₂-C₆ Alkenyl” refers to alkenyl groups preferably having from 2 to 6carbon atoms and having at least 1 or 2 sites of alkenyl unsaturation.Examples include ethenyl (—CH═CH₂), n-2-propenyl (allyl, —CH₂CH═CH₂) andthe like.

“C₃-C₆-cycloalkyl” refers to saturated or partially unsaturatedcarbocyclic rings having 3 to 6 carbon atoms. Examples includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl and thelike.

“C₃-C₆-heterocycloalkyl” refers to saturated or partially unsaturatedrings having 3 to 6 atoms and containing at least one heteroatomselected from N, S and O. Examples include pyrrolidinyl, piperidinyl,piperazinyl, imidazolidinyl, morpholinyl and the like.

“Carboxyl” means (—CO₂H).

“Carbocyclyl” means a saturated, partly saturated or unsaturated 3-12membered hydrocarbon ring, preferably a 6-12 membered hydrocarbon ring,including cycloalkyl and aryl.

“Cycloalkylamino” means —NH-(cycloalkyl).

“Cycloalkylalkylamino” means —NH-(alkyl)-(cycloalkyl), wherein alkyl andcycloalkyl are defined above. Preferably, cycloalkylalkylamino is—NHCH₂-cyclohexyl.

“Cycloalkyl” means a monocyclic or polycyclic saturated ring comprisingcarbon and hydrogen atoms and having no carbon-carbon multiple bonds.Examples of cycloalkyl groups include, but are not limited to, (C₃-C₇)cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, and cycloheptyl, and saturated cyclic and bicyclic terpenes.A cycloalkyl group can be unsubstituted or substituted. Preferably, thecycloalkyl group is a monocyclic ring or bicyclic ring.

“Di-alkylamino” means —N(alkyl)(alkyl), wherein each “alkyl” isindependently an alkyl group “Di-alkylaminoalkyl” means-(alkyl)-N(alkyl)(alkyl), wherein each “alkyl” is independently an alkylgroup.

“Di-alkylaminoalkoxy” means —O-(alkyl)N(alkyl)(alkyl), wherein each“alkyl” is independently an alkyl group “Enantiomeric excess” (ee)refers to the products that are obtained by a synthesis comprising anenantioselective step, whereby a surplus of one enantiomer in the orderof at least about 52% ee is yielded.

As used herein the phrase “an effective amount” when used in connectionwith a JNK2 inhibitor means an amount of the JNK2 inhibitor, thatproduces a measurable change of invasive, destructive, or peri-insulitisby a histological analysis of the pancreas.

“Expression” means the translation or transcription in expressing agene.

“Halogen” refers to fluoro, chloro, bromo and iodo atoms.

“Heteroaryl” refers to a monocyclic heteroaromatic, or a bicyclic or atricyclic fused-ring heteroaromatic group. Particular examples ofheteroaromatic groups include optionally substituted pyridyl, pyrrolyl,furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadia-zolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, 1,3,4-triazinyl, 1,2,3-triazinyl, benzofuryl,[2,3-dihydro]benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl,isobenzothienyl, indolyl, isoindolyl, 3H-indolyl, benzimidazolyl,imidazo[1,2-a]pyridyl, benzothiazolyl, benzoxazolyl, quinolizinyl,quinazolinyl, quinoxalinyl, cinnolinyl, pyrido[3,4-b]pyridyl,pyrido[3,2-b]pyridyl, pyrido[4,3-b]pyridyl, quinolyl, isoquinolyl,tetrazolyl, 5,6,7,8-tetrahydroquinolyl, 5,6,7,8-tetrahydroisoquinolyl,purinyl, pteridinyl, carbazolyl, xanthenyl or benzoquinolyl.

“Heteroaryl C₁-C₆-alkyl” and the like refers to C₁-C₆-alkyl groupshaving a heteroaryl substituent, including 2-furylmethyl,2-thienylmethyl, 2-(1H-indol-3-yl)ethyl and the like.

“Heteroatom-containing alkylidene” means an alkylidene wherein at leastone carbon atom is replaced by a heteroatom selected from nitrogen,oxygen, or sulfur, such as —CH₂CH₂OCH₂CH₂—, and the like, unsubstitutedor substituted with one or more alkyl groups.

“Heterocycle” means a 5- to 7-membered monocyclic, or 7- to 10-memberedbicyclic, heterocyclic ring which is either saturated, unsaturated, oraromatic, and which contains from 1 to 4 heteroatoms independentlyselected from nitrogen, oxygen and sulfur, and wherein the nitrogen andsulfur heteroatoms may be optionally oxidized, and the nitrogenheteroatom may be optionally quaternized, including bicyclic rings inwhich any of the above heterocycles are fused to a benzene ring. Theheterocycle may be attached via any heteroatom or carbon atom.Heterocycles include heteroaryls as defined above. Thus, in addition tothe heteroaryls listed above, heterocycles also include morpholinyl,pyrrolidinonyl, pyrrolidinyl, piperidinyl, hydantoinyl, valerolactamyl,oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl,tetrahydropyridinyl, tetrahydroprimidinyl, tetrahydrothiophenyl,tetrahydrothiopyranyl, tetrahydropyrimidinyl, tetrahydrothiophenyl,tetrahydrothiopyranyl, and the like.

“Heterocycloalkyl” means an alkyl having at least one alkyl hydrogenatom replaced with a heterocycle, such as —CH₂ morpholinyl, and thelike.

“Keto” means a carbonyl group.

“Inhibiting the activity of JNK2” means interacting with a JNK2 proteinor natural substrate (e.g. c-jun and JIP-1) to prevent an ordinarybiological process (e.g., c-jun phosphorylation) in vitro or in vivo.However, completely preventing the biological process from occurring isnot necessary.

The term “JNK2 inhibitor” and the like mean a compound capable ofinhibiting the activity of JNK2 in vitro or in vivo. However, completeinhibition is not required. For example, it is sufficient that theinhibitor has an IC₅₀ of less than 10 mM in a c-jun phosphorylationassay. The JNK2 inhibitor can be in the form of a pharmaceuticallyacceptable salt, free-base, solvate, hydrate, stereoisomer, clathrate orprodrug thereof. Such inhibitory activity can be determined by an assayor animal model well known in the art including those set forth in the“detailed description of the invention.”

“JNK2” means a protein or an isoform thereof expressed by a JNK2 gene.

As used herein, the term “manage” when used in connection with a diseaseor condition means to provide beneficial effects to a patient beingadministered with a prophylactic or therapeutic agent, which does notresult in a cure of the disease. In certain embodiments, a patient isadministered with one or more prophylactic or therapeutic agents tomanage a disease so as to prevent the progression or worsening of thedisease.

“Minimal effect” on activity of a protein means a compound has less thanhalf of the same effect on activity compared to another protein. Forexample, if a compound has an IC₅₀ of 1 μM for JNK2 using c-Junphosphorylation assay as described below, then the compound has minimaleffect on the inhibition of JNK1 as long as the IC₅₀ for JNK1 in thesame assay is greater than 2 μM. Such minimal effect can be determinedby an assay or animal model well known in the art including those setforth in the “detailed description of the invention.”

“Mono-alkylamino” means —NH(alkyl).

“Mono-alkylaminoalkoxy” means —O-(alkyl)-NH(alkyl), wherein each “alkyl”is independently an alkyl group.

“Mono-alkylaminoalkyl” means -(alkyl)-NH(alkyl), wherein each “alkyl” isindependently an alkyl group.

As used herein and unless otherwise indicated, the term “prodrug” meansa JNK2 inhibitor derivative that can hydrolyze, oxidize, or otherwisereact under biological conditions (in vitro or in vivo) to provide anactive compound, particularly a JNK2 inhibitor. Examples of prodrugsinclude, but are not limited to, derivatives and metabolites of a JNK2inhibitor that include biohydrolyzable moieties such as biohydrolyzableamides, biohydrolyzable esters, biohydrolyzable carbamates,biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzablephosphate analogues. Preferably, prodrugs of compounds with carboxylfunctional groups are the lower alkyl esters of the carboxylic acid. Thecarboxylate esters are conveniently formed by esterifying any of thecarboxylic acid moieties present on the molecule.

“Pharmaceutically active derivative” refers to any compound that uponadministration to the recipient, is capable of providing directly orindirectly, the activity disclosed herein.

“Pharmaceutically acceptable salts or “complexes” refers to salts orcomplexes of the below-identified compounds of formula I that retain thedesired biological activity. Examples of such salts include, but are notrestricted to acid addition salts formed with inorganic acids (e.g.hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,nitric acid, and the like), and salts formed with organic acids such asacetic acid, oxalic acid, tartaric acid, succinic acid, malic acid,fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannic acid,pamoic acid, alginic acid, poly glutamic, acid, naphthalene sulfonicacid, naphthalene disulfonic acid, and poly galacturonic acid. Saidcompounds can also be administered as pharmaceutically acceptablequaternary salts known by a person skilled in the art, whichspecifically include the quaternary ammonium salts of the formula—NR,R′,R″⁺Z⁻, wherein R, R′, R″ is independently hydrogen, alkyl, orbenzyl, and Z is a counter ion, including chloride, bromide, iodide,alkoxide, toluenesulfonate, methylsulfonate, sulfonate, phosphate, orcarboxylate (such as benzoate, succinate, acetate, glycolate, maleate,malate, fumarate, citrate, tartrate, ascorbate, cinnamoate, mandeloate,and diphenylacetate).

As used herein, the terms “prevent” and “preventing” include theprevention of the recurrence, spread or onset of type I diabetes. It isnot intended that the present invention be limited to completeprevention. In some embodiments, the onset is delayed, or the severityof the disease is reduced.

As used herein, the term “prophylactic agent” includes any agent thatcan be used in the prevention of a disease.

“Sulfonyl” refers to a group “—SO₂—R” wherein R is selected from H,“aryl”, “heteroaryl”, “C₁-C₆-alkyl”, “C₁-C₆-alkyl” which may besubstituted with halogens e.g. an —SO₂—CF₃ group, “aryl C₁-C₆-alkyl” or“heteroaryl C₁-C₆-alkyl”.

“Sulfoxy” refers to a group “—S(O)—R” wherein R is selected from H,“C₁-C₆-alkyl”, “C₁-C₆-alkyl” which may be substituted with halogens e.g.an —SO—CF₃ group, “aryl”, “heteroaryl”, “aryl C₁-C₆-alkyl” or“heteroaryl C₁-C₆-alkyl”.

“Substituted or unsubstituted” unless otherwise constrained by thedefinition of the individual substituent, the above set out groups, like“alkyl”, “Alkenyl”, “alkynyl”, “aryl” and “heteroaryl” etc. groups canoptionally be substituted with from 1 to 5 substituents selected fromthe group consisting of “C₁-C₆-alkyl”, “aryl C₁-C₆-alkyl”, “heteroarylC₁-C₆-alkyl”, “C₁-C₆-alkenyl”, “C₁-C₆-alkynyl”, primary, secondary ortertiary amino groups or quaternary ammonium moieties, “acyl”,“acyloxy”, “acylamino”, “aminocarbonyl”, “alkoxycarbonyl”, “aryl”,“heteroaryl”, carboxyl, cyano, halogen, hydroxy, mercapto, nitro,sulfoxy, sulfonyl, alkoxy, thioalkoxy, trihalomethyl and the like.Alternatively said substitution could also comprise situations whereneighboring substituents have undergone ring closure, notably whenviccinal functional substituents are involved, thus forming e.g.lactams, lactons, cyclic anhydrides, but also acetals, thioacetals,aminals formed by ring closure for instance in an effort to obtain aprotective group.

“Substituent(s)” of the “hydrocarbon group optionally havingsubstituent(s)”, or the like, means to have, oxo (═O), halogen atom(e.g., fluorine, chlorine, bromine, iodine etc.), C₁-C₃ alkylenedioxy(e.g., methylenedioxy, ethylenedioxy etc.), nitro, cyano, optionallyhalogenated C₁-C₆ alkyl, optionally halogenated C₂-C₆ alkenyl, carboxyC₂-C₆ alkenyl (e.g., 2-carboxyethenyl, 2-carboxy-2-methylethenyl etc.),optionally halogenated C₂-C₆ alkynyl, optionally halogenated C₃-C₈cycloalkyl, C₆-C₁₄ aryl (e.g., phenyl, 1-naphthyl, 2-naphthyl,2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl etc.), optionallyhalogenated C₁-C₈ alkoxy, C₁-C₆ alkoxy-carbonyl-C₁-C₆ alkoxy (e.g.,ethoxycarbonylmethyloxy etc.), hydroxy, C₆-C₁₄ aryloxy (e.g., phenyloxy,1-naphthyloxy, 2-naphthyloxy etc.), C₇-C₁₆ aralkyloxy (e.g., benzyloxy,phenethyloxy etc.), mercapto, optionally halogenated C₁-C₆ alkylthio,C₆-C₁₄ arylthio (e.g., phenylthio, 1-naphthylthio, 2-naphthylthio etc.),C₇-C₁₆ aralkylthio (e.g., benzylthio, phenethylthio etc.), amino,mono-C₁-C₆ alkylamino (e.g., methylamino, ethylamino etc.), mono-C₆-C₁₄arylamino (e.g., phenylamino, 1-naphthylamino, 2-naphthylamino etc.),di-C₁-C₆ alkylamino (e.g., dimethylamino, diethylamino, ethylmethylaminoetc.), C₃-C₈ cycloalkylamino (e.g., cyclopentylamino, cyclohexylaminoetc.), di-C₆-C₁₄ arylamino (e.g., diphenylamino etc.), formyl, carboxy,carboxy-C₁-C₆ alkyl (e.g., carboxymethyl, carboxyethyl etc.), C₁-C₆alkyl-carbonyl (e.g., acetyl, propionyl, pivaloyl etc.), C₃-C₈cycloalkylcarbonyl (e.g., cyclopropylcarbonyl, cyclopentylcarbonyl,cyclohexylcarbonyl etc.), C₁-C₆ alkoxy-carbonyl (e.g., methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl etc.), C₆-C₁₄aryl-carbonyl (e.g., benzoyl, 1-naphthoyl, 2-naphthoyl etc.), C₇-C₁₆aralkyl-carbonyl (e.g., phenylacetyl, 3-phenylpropionyl etc.), C₆-C₁₄aryloxy-carbonyl (e.g., phenoxycarbonyl etc.), C₇-C₁₆aralkyloxy-carbonyl (e.g., benzyloxycarbonyl, phenethyloxycarbonyletc.), 5- or 6-membered heterocyclic carbonyl (e.g., nicotinoyl,isonicotinoyl, thenoyl, furoyl, morpholinocarbonyl,thiomorpholinocarbonyl, piperazin-1-ylcarbonyl, pyrrolidin-1-ylcarbonyletc.), carbamoyl, thiocarbamoyl, mono-C₁-C₆ alkyl-carbamoyl (e.g.,methylcarbamoyl, ethylcarbamoyl etc.), di-C₁-C₆ alkyl-carbamoyl (e.g.,dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl etc.), mono-or di-C₆-C₁₄ aryl-carbamoyl (e.g., phenylcarbamoyl, 1-naphthylcarbamoyl,2-naphthylcarbamoyl etc.), mono- or di-5- or 6-membered heterocycliccarbamoyl (e.g., 2-pyridylcarbamoyl, 3-pyridylcarbamoyl,4-pyridylcarbamoyl, 2-thienylcarbamoyl, 3-thienylcarbamoyl etc.), C₁-C₆alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl etc.), C₁-C₆alkylsulfinyl (e.g., methylsulfinyl, ethylsulfinyl etc.), C₆-C₁₄arylsulfonyl (e.g., phenylsulfonyl, 1-naphthylsulfonyl,2-naphthylsulfonyl etc.), C₆-C₁₄ arylsulfinyl (e.g., phenylsulfinyl,1-naphthylsulfinyl, 2-naphthylsulfinyl etc.), formylamino, C₁-C₆alkyl-carbonylamino (e.g., acetylamino, propionylamino, pivaloylaminoetc.), C₃-C₈ cycloalkyl-carbonylamino (e.g., cyclopentylcarbonylamino-,cyclohexylcarbonylamino etc.), C₆-C₁₄ aryl-carbonylamino (e.g.,benzoylamino, naphthoylamino etc.), C₁-C₆ alkoxy-carbonylamino (e.g.,methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino,butoxycarbonylamino etc.), C₁-C₆ alkylsulfonylamino (e.g.,methylsulfonylamino, ethylsulfonylamino etc.), C₆-C₁₄ arylsulfonylamino(e.g., phenylsulfonylamino, 2-naphthylsulfonylamino,1-naphthylsulfonylamino etc.), C₁-C₆ alkyl-carbonyloxy (e.g., acetoxy,propionyloxy etc.), C₆-C₁₄ aryl-carbonyloxy (e.g., benzoyloxy,naphthylcarbonyloxy etc.), C₁-C₆ alkoxy-carbonyloxy (e.g.,methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy,butoxycarbonyloxy etc.), mono-C₁-C₆ alkylcarbamoyloxy (e.g.,methylcarbamoyloxy, ethylcarbamoyloxy etc.), di-C₁-C₆ alkylcarbamoyloxy(e.g., dimethylcarbamoyloxy, diethylcarbamoyloxy etc.), mono- ordi-C₆-C₁₄ aryl-carbamoyloxy (e.g., phenylcarbamoyloxy,naphthylcarbamoyloxy etc.), nicotinoyloxy, isonicotinoyloxy, 5- to7-membered saturated cyclic amino optionally having substituents, 5- to10-membered aromatic heterocyclic group (e.g., 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl,5-quinolyl, 8-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl,5-isoquinolyl, 1-indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl,2-benzo[b]thienyl, 3-benzo[b]thienyl, 2-benzo[b]furanyl,3-benzo[b]furanyl etc.), sulfo, sulfamoyl, sulfinamoyl, sulfenamoyl, agroup wherein 2 or more (e.g., 2-3) of these substituents are bonded andthe like can be mentioned.

“Selective inhibition” means that the inhibition of protein activity ofa compound on one molecular entity has a minimal effect on a secondmolecular entity.

As used herein in connection with the term “therapeutic agent”,“therapeutically effective amount” includes the amount of thetherapeutic agent sufficient to delay, reduce or minimize symptomsassociated with type I diabetes. A therapeutically effective amount alsoincludes the amount of the therapeutic agent that provides a therapeuticbenefit in the treatment or management of type I diabetes.

“Thioalkoxy” refers to groups —S—R where R includes “C₁-C₆-alkyl” or“aryl” or “heteroaryl” or “aryl C₁-C₆-alkyl” or “heteroarylC₁-C₆-alkyl”. Examples include thiomethoxy, thioethoxy, and the like.

As used herein, the term “therapeutic agent” includes any agent(s) thatcan be used in the treatment of a disease.

As used herein, the terms “treat” and “treating” are not limited to thecase where the subject (e.g. patient) is cured and the disease iseradicated. Rather, the present invention also contemplates treatmentthat merely reduces symptoms, and/or delays disease progression. Thus,in certain embodiments, treatment aids in the management or control oftype I diabetes.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to the treatment and prevention of type Idiabetes. More specifically, the invention relates to compounds thattreat or prevent the body's immune system from destroying β-cells (i.e.,insulin-producing cells in the pancreatic islets of Langerhans) byinhibition of JNK2, selective inhibition of JNK2, or inhibition of theexpression of the MAPK9 gene or gene product. In one embodiment, thepresent invention contemplates the diagnosis, identification,production, and use of compounds which modulate MAPK9 gene expression orthe activity of the MAPK9 gene product including but not limited to,JNK2, the nucleic acid encoding MAPK9 and homologues, analogues, anddeletions thereof, as well as antisense, ribozyme, triple helix,antibody, and polypeptide molecules as well as small inorganicmolecules.

The present invention contemplates a variety of pharmaceuticalformulations and routes of administration for such compounds. Thepancreas is an organ located behind the lower part of the stomach. Itmakes insulin and enzymes that help the body digest and use food. Spreadall over the pancreas are clusters of cells called the islets ofLangerhans. Islets are made up of two types of cells: alpha cells, whichmake glucagon, a hormone that raises the level of glucose (sugar) in theblood, and beta (β) cells, which make insulin. Failure of theinsulin-producing beta cells in the pancreatic islets of Langerhans is acharacteristic of type I (insulin-dependent) diabetes.

JNK1, JNK2, and JNK3 c-jun N-terminal protein kinase isoforms comprise afamily of serine/threonine protein kinases of the mitogen-activatingprotein kinase (MAPK) group. As regulators of stress-signalingresponses, JNKs play key roles in: tumor suppression, aging,neurogenesis, and immune responses. JNK2 (c-Jun N-terminal knase 2) isalso called Stress-activated protein kinase 2 (SAPK2). The JNK2 gene(MAPK9) maps on chromosome 5q35 spanning 58494 base pairs (Accession No.U09759). It contains 17 confirmed introns, 14 of which are alternative.By alternative splicing, JNK2 gene encodes 12 types of transcripts thattranslate into 12 distinct JNK2 isoforms. The molecular weight of JNK2is about 55 kD.

JNK1 is a protein comprising the amino acid sequence of GenBankAccession Number: L26318: Sequence Identification Number 1: (M S R S K RD N N F Y S V E I G D S T F T V L K R Y Q N L K P I G S G A Q G I V C AA Y D A I L E R N V A I K K L S R P F Q N Q T H A K R A Y R E L V L M KC V N H K N I I G L L N V F T P Q K S L E E F Q D V Y I V M E L M D A NL C Q V I Q M E L D H E R M S Y L L Y Q M L C G I K H L H S A G I I H RD L K P S N I V V K S D C T L K I L D F G L A R T A G T S F M M T P Y VV T R Y Y R A P E V I L G M G Y K E N V D L W S V G C I M G E M V C H KI L F P G R D Y I D Q W N K V I E Q L G T P C P E F M K K L Q P T V R TY V E N R P K Y A G Y S F E K L F P D V L F P A D S E H N K L K A S Q AR D L L S K M L V I D A S K R I S V D E A L Q H P Y I N V W Y D P S E AE A P P P K I P D K Q L D E R E H T I E E W K E L I Y K E V M D L E E RT K N G V I R G Q P S P L A Q V Q Q)

In one embodiment, JNK2 is a protein comprising the amino acid sequenceof GenBank Accession No. L3195: Sequence Identification Number 2: (M S DS K C D S Q F Y S V Q V A D S T F T V L K R Y Q Q L K P I G S G A Q G IV C A A F D T V L G I S V A V K K L S R P F Q N Q T H A K R A Y R E L VL L K C V N H K N I I S L L N V F T P Q K T L E E F Q D V Y L V M E L MD A N L C Q V I H M E L D H E R M S Y L L Y Q M L C G I K H L H S A G II H R D L K P S N I V V K S D C T L K I L D F G L A R T A C T N F M M TP Y V V T R Y Y R A P E V I L G M G Y K E N V D I W S V G C I M G E L VK G C V I F Q G T D H I D Q W N K V I E Q L G T P S A E F M K K L Q P TV R N Y V E N R P K Y P G I K F E E L F P D W I F P S E S E R D K I K TS Q A R D L L S K M L V I D P D K R I S V D E A L R H P Y I T V W Y D PA E A E A P P P Q I Y D A Q L E E R E H A I E E W K E L I Y K E V M D WE E R S K N G V V K D Q P S D A A V S S N A T P S Q S S S I N D I S S MS T E Q T L A S D T D S S L D A S T G P L E G C R).

Daxx is a Fas-binding protein that activates JNK and apoptosis asdescribed in U.S. Pat. No. 6,159,731, which is hereby incorporated byreference.

JNK2 and Type I Diabetes

Mitogen-activated protein kinases (MAPKs) form a large family ofserine-threonine protein kinases conserved through evolution. Inmammalian cells, four distinct MAPK cascades have been identified:extracellular signal-regulated kinases (ERKs), c-Jun amino-terminalkinases (JNKs) or stress-activated protein kinases (SAPKs), p38 MAPkinase (p38) or cytokine suppressive anti-inflammatory drug bindingprotein, and Erk5/BMK. JNK protein kinases are activated by dualphosphorylation on Tyr and Thr. The JNK family includes JNK1 (46 kDaisoform), JNK2 (55-kDa isoform), and JNK3. JNK1 and JNK2 areubiquitously expressed, while JNK3 is largely restricted to brain, heartand testis. Ip and Davis, Curr Opin Cell Biol. 1998 April; 10(2):205-19;Sluss et al., Mol Cell Biol. 1994 December; 14(12):8376-84. In additionto stress such as UV exposure, the JNK family is activated by cytokinesand TNF-α.

Recently, it has been suggested that JNK1, but not JNK2, is implicatedin obesity and insulin resistance associated with type II diabetes.International publication PCT (WO 02/085396), Lee et al., c-JunN-terminal kinase (JNK) mediates feedback inhibition of the insulinsignaling cascade. J Biol Chem 278, 2896-902 (2003), and Aguirre et al.,The c-Jun NH(2)-terminal kinase promotes insulin resistance duringassociation with insulin receptor substrate-1 and phosphorylation ofSer(307). J Biol Chem 275, 9047-54 (2000).

JNKs take part in the regulation of CD4+ T cell differentiation.Recently studies suggest the cooperation of CD4+ and CD8+ T cells forislet infiltration and destruction of β-cells. The cytokine environmentenables the differentiation of CD4+ T cells to two differentphenotypes: 1) Th1 cells which produce interleukin-2 (IL-2) andinterferon-γ (IFN-γ) inducing a cellular immune response or 2) Th2 cellsthat secrete IL-4, IL-5, and IL-10 which support humoral immunity anddown-regulate the inflammatory actions of Th1 cells. Benign insulitis isassociated with differentiation of CD+ T cells in a phenotype of Th2cells, whereas destructive insulitis appears to be associated with Th1cells. Pro-inflammatory cytokines produced by islet infiltrating immunecells act as effector molecules, and IL-1β in combination with IFN-γ andTNF-α triggers apoptosis of the β-cells.

The applicant has discovered that JNK2 plays role in type I(insulin-dependent) diabetes that is caused by autoimmune destruction ofβ-cells. Studies of non-obese diabetic (NOD) mice demonstrated thatdisruption of the MAPK9 gene (which encodes the JNK2 protein kinase)decreased destructive insulitis and reduced disease progression to typeI diabetes. CD4+ T cells from JNK2-deficient NOD mice produced lessIFN-γ, and significantly increased amounts of IL-4 and IL-5, indicatingpolarization towards the Th2 phenotype. This role of JNK2 to control theTh1/Th2 balance of the immune response motivated the applicant to useJNK2 inhibitors to protect against type I autoimmune diabetes.

The applicants discovered reduced insulitis and reduced progression totype I diabetes in NOD/Mapk9−/− mice. The transition from non-pathogenicinsulitis to type I diabetes correlates with the change from apredominance of Th2 to Th1 cytokines in the islets. A Th1 (IFN-γ)environment accelerates the recruitment of islet-specific CD4+ T cellsand also accelerates the onset of type I diabetes. In contrast, a Th2pancreatic environment appears to protect against autoimmune diabetes.Thus, administration of IL-4 systemically or expression of IL-4 in NODmice in vivo interferes with the islet infiltration by T cells andprevents Th1-mediated destructive insulitis and type I diabetes. Theobservation that JNK2-deficiency causes selective polarization of CD4+ Tcells to the Th2 phenotype with increased IL-4 expression can lead tocreation of a Th2 pancreatic environment that protects againstautoimmune diabetes. Thus, one embodiment of the current invention isthe treatment and prevention of type I diabetes by administering to asubject an inhibitor of JNK2. In further embodiments, the JNK2 inhibitorselectively inhibits JNK2.

Inappropriate activation of T cells initiates many autoimmune diseases.Although, the applicant does not desire the invention to be limited toany particular mechanism, JNK2 inhibitors may play several roles inpreventing type I diabetes. JNK2 inhibitors may play a suppressive rolein autoimmune disease by causing a negative selection of autoreactive Tcells in the thymus. In type I diabetes, JNK2 inhibitors may preventbeta-cell apoptosis caused by cytokines and oxidative stress caused byreactive oxygen species and nitric oxide. Furthermore, JNK2 inhibitorsmay prevent the production of macrophage-derived cytokines, includingTNF-α, contributing to the development of destructive insulitis anddiabetes. It is possible that JNK2 inhibitors act in multiple ways asthose mentioned or those not mentioned.

JNK2 Inhibitors

The present invention is direct to methods useful for treating orpreventing type I diabetes in a subject, comprising administering aneffective amount of a JNK2 inhibitor or selective JNK2 inhibitor.Illustrative JNK2 inhibitors and JNK2 selective inhibitors are set forthbelow.

Antisense oligonucleotides of JNK2 have been described in U.S. Pat. Nos.6,221,850 and 6,133,246, which are hereby incorporated by reference.Oligonucleotides that are specifically hybridizable with nucleic acidsencoding JNK2 are JNK2 inhibitors. Embodiments include oligonucleotidescomprising up to 30 nucleotides (typically between 15 and 25nucleotides) in length wherein said oligonucleotides have a sequencethat specifically binds to nucleic acids encoding JNK2 (e.g. human MAPK9gene, GenBank Accession number NC 000005 and any corresponding mRNA).Further illustrative embodiments can be found in the correspondingpatents provided above. JNK-interacting protein-1 (JIP-1) was firstidentified as a direct binding partner for JNK1 in yeast two-hybridanalysis. The specificity of interactions was underlined by JIP-1interacting with JNK1, JNK2, and JNK3, but not ERK or p38 MAPKs, andfailing to alter the activity of these two closely related MAPKs.Furthermore, JNKs bound to JIP-1 with greater affinity than itstranscription factor substrates, c-Jun and activating transcriptionfactor-2 (ATF2). A number of amino acid sequences based on the bindingdomain of JIP-1, JIP-2, and c-Jun have been disclosed as JNK inhibitorsincluding those disclosed in WO 03/103698, U.S. Pat. No. 6,780,970, andU.S. Patent Application Publication 2002/0119135, all of which or anypresent or future corresponding U.S. application or patent are herebyincorporated by reference. Examples of JNK2 inhibitor peptides include apeptide which includes (in whole or in part) the sequenceNH₂-DTYRPKRPTTLNLFPQVPRSQDT-COOH [SEQ ID NO:3]. In another embodiment,the peptide includes the sequence NH₂-EEPHKHRPTTLRLTTLGAQDS-COOH [SEQ IDNO:4]. In another embodiment, the peptide includes the sequenceNH2-FLNLTTPRKPR-COOH [SEQ ID NO:5]. In another embodiment the peptideincludes the sequence NH₂-FLNLTTPRKPRYTDGSGTGPG-COOH [SEQ ID NO:6].Further illustrative embodiments can be found in the identifiedreferences.

The JNK2 inhibitor peptides can be polymers of L-amino acids, D-aminoacids, or a combination of both. For example, in various embodiments,the peptides are D retro-inverso peptides. The term “retro-inversoisomer” refers to an isomer of a linear peptide in which the directionof the sequence is reversed and the chirality of each amino acid residueis inverted. The net result of combining D-enantiomers and reversesynthesis is that the positions of carbonyl and amino groups in eachamide bond are exchanged, while the position of the side-chain groups ateach alpha carbon is preserved. Unless specifically stated otherwise, itis presumed that any given L-amino acid sequence of the invention may bemade into a D retro-inverso peptide by synthesizing a reverse of thesequence for the corresponding native L-amino acid sequence.

The following sulfonamide derivatives are contemplated for use astherapeutics in treating type I diabetes:

wherein: Ar¹ is a substituted or unsubstituted aryl or heteroaryl group;X is O or S; Ar² a substituted or unsubstituted aryl or heteroarylgroup; R¹ and R² are independently selected from the group consisting ofhydrogen and a C₁-C₆-alkyl group; R^(a), R^(a′), R^(b), R^(b′) areindependently selected from the group consisting of hydrogen andC₁-C₆-alkyl; or R^(a′) and R^(a) or R^(b′) together with the carbonatoms they are linked, form a substituted or unsubstituted 5-8-memberedsaturated, partially unsaturated or aromatic ring containing optionallyone or more heteroatoms selected from O, N, S; R³ is selected from thegroup consisting of H, C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkynyl,aryl, heteroaryl, 3-8 membered cycloalkyl optionally containing 1-3heteroatoms selected from the group consisting of N, O, and S; arylC₁-C₁₀-alkyl and heteroaryl C₁-C₁₀-alkyl; or R³ and R^(a) or R^(a′)form, together with the N atom linked to R³, a 5-8-membered saturatedring, containing optionally at least one further heteroatom selectedfrom O, N, S; R⁴ is selected from the group consisting of H and—C(H)R⁵R⁶; R⁵ and R⁶ are independently selected from the groupconsisting of H, C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkynyl, aryl,heteroaryl, 3-8 membered cycloalkyl optionally containing 1-3heteroatoms selected from the group consisting of N, O, and S; arylC₁-C₁₀-alkyl and heteroaryl C₁-C₁₀-alkyl; m is an integer from 1 to 5; nis an integer from 0 to 2; and p is an integer from 1 to 10. Thesecompounds have been described in United States Patent ApplicationPublication US 2004/0248886 as particular efficient and selectiveinhibitors of JNK2, and this publication or any present or futurecorresponding U.S. application or patent are hereby incorporated byreference.

Preferred embodiments include compounds of the following formula:

Further illustrative embodiments can be found in the identifiedreference.

The following sulfonamide derivatives are contemplated for use astherapeutics in treating type I diabetes:

wherein Ar¹ and Ar² are independently from each other substituted orunsubstituted aryl or heteroaryl groups; X is O or S, preferably O; R¹is hydrogen or a C₁-C₆ alkyl group, or R¹ forms a substituted orunsubstituted 5-6 membered saturated or unsaturated ring with Ar¹; n isan integer from 0 to 5, preferably between 1-3 and most preferred 1; Yis an unsubstituted or a substituted 4-12 membered saturated cyclic orbicyclic alkyl containing at least one nitrogen atom, whereby onenitrogen atom within said ring is forming a bond with the sulfonyl groupthus providing a sulfamide. These compounds have been described in PCTInternational Publication Number WO 01/23378 as particular efficient andselective inhibitors of JNK2, and this publication or any present orfuture corresponding U.S. application or patent are hereby incorporatedby reference. Preferred embodiments include:

-   4-chloro-N-[(5-{[4-(2,4-difluorobenzoyl)piperidin-1-yl]sulfonyl}thien-2-yl)methyl]benzamide;-   4-chloro-N-[(5-{[4-(phenylacetyl)-1,4-diazepan-1-yl]sulfonyl}thien-2-yl)methyl]benzamide;-   N-({5-[(4-anilinopiperidin-1-yl)sulfonyl]thien-2-yl}methyl)-4-chlorobenzamide;-   N-[(5-{[4-(1H-1,2,3-benzotriazol-1-yl)piperidin-1-yl]sulfonyl}thien-2-yl)methyl]-4-chlorobenzamide;-   N-[(5-{[4-(1H-benzimidazol-1-yl)piperidin-1-yl]sulfonyl}thien-2-yl)methyl]-4-chlorobenzamide;-   4-chloro-N-{[5-({4-[3-propylanilino]piperidin-1-yl}sulfonyl)thien-2-yl]methyl}benzamide;-   4-chloro-N-[(5-{[4-(4-chloroanilino)piperidin-1-yl]sulfonyl}thien-2-yl)methyl]benzamide;-   4-chloro-N-({5-[(4-{3-[(2-hydroxyethyl)sulfonyl]anilino}piperidin-1-yl)sulfonyl]thien-2-yl}methyl)benzamide;-   N-{[5-({4-[3-(aminosulfonyl)anilino]piperidin-1-yl}sulfonyl)thein-2-yl]methyl}-4-chlorobenzamide;-   4-chloro-N-[(5-{[4-(1-naphtholyl)piperazin-1-yl]sulfonyl}thien-2-yl)methyl]benzamide;-   4-nitro-N-[(5-{[4-(3-methoxyanilino)piperidin-1-yl]sulfonyl}thien-2-yl)methyl]benzamide;-   methyl    3-{[1-({5-[({4-nitrobenzoyl}amino)methyl]thien-2-yl}sulfonyl)piperidin-4-yl]amino}benzoate;-   N-[(5-{[4-(1H-1,2,3-benzotriazol-1-yl)piperidin-1-yl]sulfonyl}thein-2-yl)methyl]-2-hydroxybenzamide;-   N-({5-[(4-{2-nitroanilino}piperidin-1-yl)sulfonyl]thien-2-yl}methyl)-3-methoxybenzamide.    Further illustrative embodiments can be found in the identified    reference.

The following sulfonyl derivatives are contemplated for use astherapeutics in treating type I diabetes:

wherein Ar¹ and Ar² are independently from each other substituted orunsubstituted aryl or heteroaryl groups; X is O or S, preferably O; R¹is hydrogen or a C₁-C₆ alkyl group, preferably hydrogen; alternatively,R¹ forms a substituted or unsubstituted 5-6 membered saturated orunsaturated fused ring with Ar¹; According to a further alternative R2and R4 could form a substituted or unsubstituted 5-6-membered saturatedor unsaturated ring. R² is hydrogen, or a substituted or unsubstitutedC₁-C₆-alkyl, preferably hydrogen; n is an integer from 0 to 5,preferably between 1-3 and most preferred 1; R₃ and R₄ are independentlyfrom each other selected form the group comprising or consisting ofnatural or synthetic amino acid residues, hydrogen, substituted orunsubstituted C₁-C₆-alkyl, like trihalomethyl, substituted orunsubstituted C₁-C₆ alkoxy, NH₂, SH, C₁-C₆-thioalkyl, acylamino,aminocarbonyl, substituted or unsubstituted C₁-C₆-alkoxycarbonyl, aryl,heteroaryl, substituted or unsubstituted 4-8-membered cyclic alkyl,optionally contain 1-3 heteroatoms, carboxyl, cyano, halogen, hydroxyl,nitro, acyloxy, sulfoxy, sulfonyl C₁-C₆-thioalkoxy, whereby though, atleast one of R₃ and/or R₄ must be an amino acid residue; R⁵ is H orsubstituted or unsubstituted C₁-C₆-alkyl; R⁶ is selected from the groupcomprising or consisting of substituted or unsubstituted C₁-C₆ aliphaticalkyl, substituted or unsubstituted saturated cyclic C₄-C₈-alkyloptionally containing 1-3 heteroatoms and optionally fused with an arylor an heteroaryl; or R⁶ is a substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl whereby said aryl or heteroarylgroups are optionally substituted or unsubstituted C₁-C₆-alkoxy,substituted or unsubstituted C₂-C₆ alkenyl, substituted or unsubstitutedC₂-C₆ alkynyl, amino acylamino aminocarbonyl, substituted orunsubstituted C₁-C₆-alkoxycarbonyl, aryl, carboxyl, cyano, halogen,hydroxy, nitro, acyloxy, acylamino, sulfoxy, sulfonyl, C₁-C₆-thioalkoxyor; or R⁵ and R⁶ taken together form a substituted or unsubstituted4-8-membered saturated cyclic alkyl or heteroalkyl group. Thesecompounds have been described in PCT International Publication Number WO01/23379 as particular efficient and selective inhibitors of JNK2, andthis publication or any present or future corresponding U.S. applicationor patent are hereby incorporated by reference. Preferred embodimentsinclude:

-   4-chloro-N-({5-[({2-[(2-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}ethyl)amino]-2-oxoethyl}amino)sulfonyl]thien-2-yl}methyl)benzamide    and-   4-chloro-N-[(5-{[(2-oxo-2-{3-{(trifluoromethyl)sulfonyl]anilino}ethyl)amino]sulfonyl}thien-2-yl)methyl]benzamide.    Further illustrative embodiments can be found in the identified    reference.

The following sulfonyl hydrazine derivatives are contemplated for use astherapeutics in treating type I diabetes:

wherein Ar¹ and Ar² are independently from each other substituted orunsubstituted aryl or heteroaryl groups; X¹ and X² are independentlyfrom each other O or S; R¹, R², and R³ are independently from each otherhydrogen or a C₁-C₆ alkyl substituent or R¹ forms a substituted orunsubstituted 5-6-membered saturated or unsaturated ring with Ar¹; or R²and R³ form a substituted or unsubstituted 5-6-membered saturated orunsaturated ring; n is an integer from 0 to 5; G is selected from agroup comprising or consisting of an unsubstituted or substituted4-8-membered heterocycle containing at least one heteroatom, or G is asubstituted or unsubstituted C₁-C₆ alkyl group. These compounds havebeen described in PCT International Publication Number WO 01/23382 asparticular efficient and selective inhibitors of JNK2, and thispublication or any present or future corresponding U.S. application orpatent are hereby incorporated by reference. Preferred embodimentsinclude:

-   4-chloro-N-(4-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)hydrazino]sulfonyl}benzyl)benzamide;-   N-[(5-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)hydrazino]sulfonyl}thien-2-yl)methyl]-2-oxo-1,2-dihydropyridine-3-carboxamide;-   N-[(5-{[2-(4-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}butanoyl)hydrazino]sulfonyl}thien-2-yl)methyl]-2-hydroxybenzamide;-   4-chloro-N-[(5-{[2-({2-[(2-chlorophenoxy)methyl]-1,3-thiazol-4-yl}carbonyl)hydrazino]sulfonyl}thien-2-yl)methyl]benzamide-   4-chloro-N-[(5-{[2-({2-[4-(1,3-dithiolan-2-yl)phenyl]-1,3-thiazol-4-yl}carbonyl)hydrazino]sulfonyl}thien-2-yl)methyl]benzamide.    Further illustrative embodiments can be found in the identified    reference.

The following derivatives are contemplated for use as therapeutics intreating type I diabetes:

Wherein Z¹¹ and Z¹² each independently represent a carbonyl group, anoxygen atom, a sulfur atom, a methine group which may be substituted, amethylene group which may be substituted or a nitrogen atom which may besubstituted;

represents a double bond or a single bond; R^(1a) represents a hydrogenatom, a C₁-C₆ alkyl group, a phenyl group or a benzyl group; R^(2a),R^(2b) and R^(2c) each independently represent a group selected from thefollowing Substituent Group (a); the ring A represents a benzene ringwhich may have one to three groups selected from the followingSubstituent Group (a), a naphthalene ring which may have one to threegroups selected from the following Substituent Group (a) or a 5- to10-membered aromatic heterocyclic ring which may have one to threegroups selected from the following Substituent Group (a); SubstituentGroup (a) (1) a hydrogen atom, (2) halogen atoms, (3) a nitro group, (4)a hydroxyl group, (5) a cyano group, (6) a carboxyl group, (7) an aminogroup, (8) a formyl group or (9) a group represented by the formula:

wherein X¹ and X² each independently represent a single bond, —CO—,—SO₂— or C₁-C₆-methylene group; X³ represents a single bond, —CO—, —SO₂,—O—, —CO—O— or —O—CO—; R^(3b) represents a C₁-C₆ alkylene group or asingle bond; R^(3a) and R^(3c) represent a hydrogen atom, a C₁-C₆ alkylgroup which may be substituted, a C₂-C₆ alkenyl group which may besubstituted, a C₂-C₆ alkynyl group which may be substituted, a C₃-C₈cycloalkyl group which may be substituted, a C₆-C₁₄ aromatic cyclichydrocarbon group which may be substituted, a 5- to 14-membered aromaticheterocyclic group which may be substituted or a hydrogen atom. Thesecompounds have been described in PCT International Publication Number WO03/072550, and this publication or any present or future correspondingU.S. application or patent are hereby incorporated by reference.Preferred embodiments include:

Further illustrative embodiments can be found in the identifiedreferences.

The following derivatives are contemplated for use as therapeutics intreating type I diabetes:

wherein: A is a direct bond, —(CH₂)_(a)—, —(CH₂)_(b)CH═CH(CH₂)_(c)—, or—(CH₂)_(b)C≡C(CH₂)_(c)—; R¹ is aryl, heteroaryl or heterocycle fused tophenyl, each being optionally substituted with one to four substituentsindependently selected from R³; R² is —R³, —R⁴, —(CH₂)_(b)C(═O)R⁵,—(CH₂)_(b)C(═O)OR⁵, —(CH₂)_(b)C(═O)NR⁵R⁶,—(CH₂)_(b)C(═O)NR₅(CH₂)CC(═O)R⁶, —(CH₂)_(b)NR⁵C(═O)R⁶,—(CH₂)_(b)NR⁵C(═O)NR⁶R⁷, —(CH₂)_(b)NR⁵R⁶, —(CH₂)_(b)OR⁵,—(CH₂)_(b)SO_(d)R⁵ or —(CH₂)_(b)SO₂NR⁵R⁶; a is 1, 2, 3, 4, 5 or 6; b andc are the same or different and at each occurrence independentlyselected from 0, 1, 2, 3 or 4; d is at each occurrence 0, 1 or 2; R³ isat each occurrence independently halogen, hydroxy, carboxyl, alkyl,alkoxy, haloalkyl, acyloxy, thioalkyl, sulfinylalkyl, sulfonylalkyl,hydroxyalkyl, aryl, arylalkyl, heterocycle, heterocycloalkyl, —C(═O)OR⁸,—OC(═O)R⁸, —C(═O)NR⁸R⁹, —C(═O)NR⁸R⁹, —SO₂NR⁸R⁹, —NR⁸SO₂R⁹, —CN, —NO₂,—NR⁸R⁹, —NR⁸C(═O)R⁹, —NR⁸C(═O)(CH₂)_(b)OR⁹, —NR⁸C(═O)(CH₂)_(b)R⁹,—O(CH₂)_(b)NR⁸R⁹, or heterocycle fused to phenyl; R⁴ is alkyl, aryl,arylalkyl, heterocycle or heterocycloalkyl, each being optionallysubstituted with one to four substituents independently selected fromR³, or R⁴ is halogen or hydroxy; R⁵, R⁶ and R⁷ are the same or differentand at each occurrence independently hydrogen, alkyl, aryl, arylalkyl,heterocycle or heterocycloalkyl, wherein each of R⁵, R⁶ and R⁷ areoptionally substituted with one to four substituents independentlyselected from R³; and R⁸ and R⁹ are the same or different and at eachoccurrence independently hydrogen, alkyl, aryl, arylalkyl, heterocycle,or heterocycloalkyl, or R⁸ and R⁹ taken together with the atom or atomsto which they are bonded form a heterocycle, wherein each of R⁸, R⁹, andR⁸ and R⁹ taken together to form a heterocycle are optionallysubstituted with one to four substituents independently selected fromR³. These compounds have been described in PCT International PublicationNumber WO 02/10137, as well as, U.S. Patent Application Publication2004/0077877 and 2004/0127536 as particular efficient and selectiveinhibitors of JNK2, all of which or any present or future correspondingU.S. application or patent are hereby incorporated by reference.Preferred embodiments include:

Further illustrative embodiments can be found in the identifiedreference(s).

The following derivatives are contemplated for use as therapeutics intreating type I diabetes:

wherein R¹ is aryl or heteroaryl optionally substituted with one to foursubstituents independently selected from R⁷; R² is hydrogen; R³ ishydrogen or lower alkyl; R⁴ represents one to four optionalsubstituents, wherein each substituent is the same or different andindependently selected from halogen, hydroxy, lower alkyl and loweralkoxy; R⁵ and R⁶ are the same or different and independently —R⁸,—(CH₂)_(a)C(═O)R⁹, —(CH2)_(a)C(═O)OR⁹, —(CH2)_(a)C(═O)NR⁹R¹⁰,—(CH2)_(a)C(═O)NR⁹(CH2)_(b)C(═O)R¹⁰, —(CH2)_(a)NR⁹C(═O)R¹⁰,(CH2)_(a)NR¹¹C(═O)NR⁹R¹⁰, —(CH2)_(a)NR⁹R¹⁰, —(CH2)_(a)OR⁹,—(CH2)_(a)SO_(c)R⁹ or —(CH2)_(n)SO2NR⁹R¹⁰; or R⁵ and R⁶ taken togetherwith the nitrogen atom to which they are attached to form a heterocycleor substituted heterocycle; R⁷ is at each occurrence independentlyhalogen, hydroxy, cyano, nitro, carboxyl, alkyl, alkoxy, haloalkyl,acyloxy, thioalkyl, sulfinylalkyl, sulfonylalkyl, hydroxyalkyl, aryl,arylalkyl, heterocycle, substituted heterocycle, heterocycloalkyl,—C(═O)OR⁸, —OC(═O)R⁸, —C(═O)NR⁸R⁹, —C(═O)NR⁸OR⁹, —SO_(c)R⁸,—SO_(c)NR⁸R⁹, —NR⁸SOR⁹, —NR⁸R⁹, —NR⁸C(═O)R⁹, —NR⁸C(═O)(CH₂)bOR⁹,—NR⁸C(═O)(CH2)_(b)R⁹, —O(CH2)_(b)NR⁸R⁹, or heterocycle fused to phenyl;R⁸, R⁹, R¹⁰ and R¹¹ are the same or different and at each occurrenceindependently hydrogen, alkyl, aryl, arylalkyl, heterocycle,heterocycloalkyl; or R⁸ and R⁹ taken together with the atom or atoms towhich they are attached to form a heterocycle; a and b are the same ordifferent and at each occurrence independently selected from 0, 1, 2, 3or 4; and c is at each occurrence 0, 1 or 2. These compounds have beendescribed in PCT International Publication Number WO 02/46170, as wellas U.S. Patent Application Publication 2004/01066634 as particularefficient and selective inhibitors of JNK2, and all of which or anypresent or future corresponding U.S. application or patent are herebyincorporated by reference. Preferred embodiments include:

Further illustrative embodiments can be found in the identifiedreference.

The following derivatives are contemplated for use as therapeutics intreating type I diabetes:

wherein R⁰ is —O—, —S—, —S(O)—, —S(O)₂—, NH or —CH₂—; being: (i)unsubstituted, (ii) monosubstituted and having a first substituent, or(iii) disubstituted and having a first substituent and a secondsubstituent; the first or second substituent, when present, is at the 3,4, 5, 7, 8, 9, or 10 position, wherein the first and second substituent,when present, are independently alkyl, hydroxy, halogen, nitro,trifluoromethyl, sulfonyl, carboxyl, alkoxycarbonyl, alkoxy, aryl,aryloxy, arylalkyloxy, arylalkyl, cycloalkylalkyloxy, cycloalkyloxy,alkoxyalkyl, alkoxyalkoxy, aminoalkoxy, mono-alkylaminoalkoxy,di-alkylaminoalkoxy, —NHR³R⁴, —NH(CH₂)_(n)NR³R⁴, —NH(═O)R⁵, —NHSO₂R⁵,—C(═O)NR³R⁴, or —SO₂NR³R⁴; wherein n is 0-6, R³ and R⁴ are takentogether and represent alkylidene or a heteroatom-containing cyclicalkylidene or R³ and R⁴ are independently hydrogen, alkyl, cycloalkyl,aryl, arylalkyl, cycloalkylalkyl, aryloxyalkyl, alkoxyalkyl, aminoalkyl,mono-alkylaminoalkyl, or di-alkylaminoalkyl; and R⁵ is hydrogen, alkyl,cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl,alkoxycarbonylalkyl, amino, mono-alkylamino, di-alkylamino, arylamino,arylalkylamino, cycloalkylamino, cycloalkylalkylamino, aminoalkyl,mono-alkylaminoalkyl, or di-alkylaminoalkyl. These compounds have beendescribed in PCT International Publication Number WO 01/12609, as wellas WO 02/066450, as well as U.S. Patent Application Publication2004/0092562 and all of which or any present or future correspondingU.S. application or patent are hereby incorporated by reference.Preferred embodiments include:

Further illustrative embodiments can be found in the identifiedreference(s).

The following derivatives are contemplated for use as therapeutics intreating type I diabetes:

wherein N¹ is a nitrogen atom optionally having a substituent or ahydrogen atom, X¹ is (i) a carbon atom optionally having substituent(s)or hydrogen atom(s), (ii) an oxygen atom, (iii) a sulfur atom or (iv) anitrogen atom optionally having a substituent or a hydrogen atom, X² is(i) a carbon atom optionally having substituent(s) or hydrogen atom(s),(ii) an oxygen atom, (iii) a sulfur atom or (iv) a nitrogen atomoptionally having a substituent or a hydrogen atom, X³ is (i) a carbonatom or (ii) a nitrogen atom, wherein (1) when X¹ is an oxygen atom or asulfur atom, X² is a carbon atom optionally having substituent(s) orhydrogen atom(s), X³ is a carbon atom and N¹ is a nitrogen atom, (2)when X¹ is a nitrogen atom having a substituent or a hydrogen atom andX³ is a carbon atom, X2 is a carbon atom optionally havingsubstituent(s) or hydrogen atom(s) and N¹ is a nitrogen atom, (3) whenX¹ and X³ are each a nitrogen atom, X² is a carbon atom optionallyhaving substituent(s) or hydrogen atom(s), and N¹ is a nitrogen atom,(4) when X¹ is a carbon atom optionally having substituent(s) orhydrogen atom(s) and X² is an oxygen atom or a sulfur atom, X³ is acarbon atom and N¹ is a nitrogen atom, (5) when X¹ is a carbon atomoptionally having substituent(s) or hydrogen atom(s) and X³ is a carbonatom, one of N¹ and X² is a nitrogen atom, and the other is a nitrogenatom having a substituent or a hydrogen atom, (6) when X¹ and X² areeach a carbon atom optionally having substituent(s) or hydrogen atom(s)and X³ is a carbon atom, N¹ is a nitrogen atom having a substituent or ahydrogen atom, and (7) when X¹ and X² are each a carbon atom optionallyhaving substituent(s) or hydrogen atom(s) and X³ is a nitrogen atom, N¹is a nitrogen atom, ring A optionally further has substituent(s), ring Bis an aromatic ring, Y is (i) a carbon atom optionally havingsubstituent(s) or hydrogen atom(s) or (ii) a nitrogen atom, Z is a bond,—NR⁴—(R⁴ is a hydrogen atom or a hydrocarbon group optionally havingsubstituent(s)), an oxygen atom or an optionally oxidized sulfur atom, Wis a bond or a divalent hydrocarbon group optionally havingsubstituent(s), R² is an aromatic group optionally havingsubstituent(s), and R³ is a hydrocarbon group optionally havingsubstituent(s) or a heterocyclic group optionally having substituent(s).These compounds have been described in U.S. Patent ApplicationPublication 2004/0063946 and all of which or any present or futurecorresponding U.S. application or patent are hereby incorporated byreference. Preferred embodiments include:

-   4-[4-(3-methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-pyridylamine;-   [5-(2-cyclohexylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]amine;-   [5-(2-cyclopentylamino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]amine;-   4-[4-(3-chlorophenyl)-2-ethyl-1,3-thiazol-5-yl]-N-[(1S)-1-phenylethyl]-2-Pyridylamine    Hydrochloride;-   N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]Phenylacetamide;-   N-[4-[4-(4-chlorophenyl)-2-ethyl-1,3-thiazol-5-yl]-2-pyridyl]benzamide;-   N-[4-[2-ethyl-4-(4-fluoro-3-methyl-phenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide.    Further illustrative embodiments can be found in the identified    reference(s).

The following derivatives are contemplated for use as therapeutics intreating type I diabetes:

wherein: W is nitrogen or CH; G is hydrogen or C₁₋₃ aliphatic whereinone methylene unit of G is optionally replaced by —C(O)—, —C(O)O—,—C(O)NH—, —SO₂—, or —SO₂NH—; A is —N-T_((n))-R, oxygen, or sulfur; R¹ isselected from -T_((n))-R or -T_((n)-Ar) ¹; each n is independently 0 or1; T is a C₁₋₄ alkylidene chain wherein one methylene unit of T isoptionally replaced by —C(O)—, —C(O)O—, —C(O)NH—, —SO₂—, or —SO₂NH—; Ar¹is a 3-7 membered monocyclic saturated, partially saturated or aromaticring having 0-3 heteroatoms independently selected from nitrogen,oxygen, or sulfur, or a 8-10 membered bicyclic saturated, partiallysaturated or aromatic ring having 0-5 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, wherein each member of Ar¹ isoptionally substituted with one —Z—R³ and one to three additional groupsindependently selected from —R, halogen, oxo, —NO₂, —CN, —OR, —SR,—N(R)₂, —NRC(O)R, —NRC(O)N(R)₂, —NRCO₂R, —C(O)R, —CO₂R, —OC(O)R,—C(O)N(R)₂, —OC(O)N(R)₂, —S(O)R, —SO₂R, —SO₂N(R)₂, —NRSO₂R, —NRSO₂N(R)₂,—C(O)C(O)R, or —C(O)CH₂C(O)R; each R is independently selected fromhydrogen or a C₁₋₆ aliphatic, wherein said aliphatic is optionallysubstituted with one to three groups independently selected from oxo,—CO₂R′, —OR′, —N(R′)₂, —SR′, —NO₂, —NR′C(O)R′, —NR′C(O)N(R′)₂,—NR′CO₂R′, —C(O)R′, —OC(O)R′, —C(O)N(R′)₂, —OC(O)N(R′)₂, —S(O)R′,—SO₂R′, —SO₂N(R′)₂, —NR′SO₂R′, —NR′SO₂N(R′)₂, —C(O)C(O)R′,—C(O)CH₂C(O)R′, halogen, or —CN, or two R bound to the same nitrogenatom are taken together with that nitrogen atom to form a five or sixmembered heterocyclic or heteroaryl ring having one to two additionalheteroatoms independently selected from oxygen, nitrogen, or sulfur;each R′ is independently selected from hydrogen or C₁₋₆ aliphatic,wherein said aliphatic is optionally substituted with one to threegroups independently selected from oxo, —CO₂H, —OH, —NH₂, —SH, —NO₂,—NHC(O)H, —NHC(O)NH₂, —NHCO₂H, —C(O)H, —OC(O)H, —C(O)NH₂, —OC(O)NH₂,—S(O)H, —SO₂H, —SO₂NH₂, —NHSO₂H, —NHSO₂NH₂, —C(O)C(O)H, —C(O)CH₂C(O)H,halogen, or —CN, or two R′ bound to the same nitrogen atom are takentogether with that nitrogen atom to form a five or six memberedheterocyclic or heteroaryl ring optionally having one or two additionalheteroatoms independently selected from nitrogen, oxygen, or sulfur; Zis a C₁-C₆ alkylidene chain wherein up to two nonadjacent methyleneunits of Z are optionally replaced by —C(O)—, —C(O)O—, —C(O)C(O)—,—C(O)N(R)—, —OC(O)N(R)—, —N(R)N(R)—, —N(R)N(R)C(O)—, —N(R)C(O)—,—N(R)C(O)O—, —N(R)C(O)N(R)—, —S(O)—, —SO₂—, —N(R)SO₂—, —SO₂N(R)—,—N(R)SO₂N(R)—, —O—, —S—, or —N(R)—; R² is -Q_((n))-Ar²; Ar² is selectedfrom a 3-7 membered monocyclic saturated, saturated or aromatic ringhaving 0-3 heteroatoms independently selected from nitrogen, oxygen, orsulfur, or a 8-10 membered bicyclic saturated, saturated or aromaticring having 0-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur, wherein each member of Ar² is optionally substitutedwith 1-5 groups independently selected from —Z—R³, —R, halogen, oxo,—NO2, —CN, —OR, —SR, —N(R)₂, NRC(O)R, —NRC(O)N(R)₂, —NRCO₂R, —C(O)R,—CO₂R, OC(O)R, —C(O)N(R)₂, —OC(O)N(R)₂, —S(O)R, —SO₂R, SO₂N(R)₂,—N(R)SO₂R, —N(R)SO₂N(R)₂, —C(O)C(O)R, or —C(O)CH₂C(O)R; Q is a C₁₋₃alkylidene chain wherein up to two nonadjacent methylene units of Q areoptionally replaced by —C(O)—, —C(O)O—, —C(O)C(O)—, —C(O)N(R)—,—OC(O)N(R)—, —N(R)N(R)—, —N(R)N(R)C(O)—, —N(R)C(O)—, —N(R)C(O)O—,—N(R)C(O)N(R)—, —S(O)—, —SO₂—, —N(R)SO₂—, —SO₂N(R)—, —N(R)SO₂N(R)—, —O—,—S—, or —N(R)—; R³ is selected from —Ar³, —R, halogen, —NO₂, —CN, —OR,—SR, —N(R)₂, —NRC(O)R, —NRC(O)N(R)₂, —NRCO₂R, —C(O)R, —CO₂R, —OC(O)R,—C(O)N(R)₂, —OC(O)N(R)₂, —SOR, —SO₂R, —SO₂N(R)₂, —NRSO₂R, —NRSO₂N(R)₂,—C(O)C(O)R, or —C(O)CH₂C(O)R; and Ar³ is a 5-6 membered saturated,partially saturated, or aromatic ring having 0-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, wherein eachmember of Ar³ is optionally substituted with halogen, oxo, —CN, —NO₂,—R′, —OR′, —N(R′)₂, —N(R′)C(O)R′, N(R′)C(O)N(R′)₂, —N(R′)CO₂R′, —C(O)R′,—CO₂R′, OC(O)R′, —C(O)N(R′)₂, —OC(O)N(R′)₂, or —SO₂R′; provided thatwhen W is nitrogen and: (i) A is —N-T_((n))-R and R2 is a saturated ringor (ii) A is sulfur, then R¹ is other than an optionally substitutedphenyl. These compounds have been described in U.S. Patent ApplicationPublication 2004/0097531 and all of which or any present or futurecorresponding U.S. application or patent are hereby incorporated byreference. Preferred embodiments include:

Further illustrative embodiments can be found in the identifiedreference.

The following derivatives are contemplated for use as therapeutics intreating type I diabetes:

wherein R¹ is optionally substituted carbocyclyl or heterocyclyl group,R² is an optionally substituted five or six membered heterocyclyl groupor an optionally substituted six membered carbocyclyl group, E ishydrogen, halogen cyano, C₁₋₆ alkoxyl or C₁₋₆ alkyl, G is hydrogen,halogen, cyano, C₁₋₆ alkoxy or C₁₋₆ alkyl, and L is hydrogen, halogen,cyano, C₁₋₆ alkoxy or C₁₋₆ alkyl. These compounds have been described inInternational Publication Number WO 2004/078756 and all of which or anypresent or future corresponding U.S. application or patent are herebyincorporated by reference. Preferred embodiments include:

Further illustrative embodiments can be found in the identifiedreference.

The following derivatives are contemplated for use as therapeutics intreating type I diabetes:

wherein R¹ is an optionally substituted C₃₋₁₆ carbocyclyl or C₃₋₁₂heterocyclyl group, Y is N or C and Z is lone electron pair, hydrogen,C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₁₋₁₂ haloalkyl, C₃₋₁₂carbocyclyl, C₃₋₁₂ heterocyclyl, —(CH₂)_(n)OR², —(CH₂)_(n)NR² ₂, —CO₂R²,—COR², —CONR² ₂, wherein the C₁₋₁₂ alkyl group optionally contains oneor more insertions selected from —O—, —N(R²)—, —S—, —SO—, —SO₂—; andeach substitutable nitrogen atom in Z is optionally substituted by —R³,—COR³, —SO₂R³ or —CO₂R³; wherein n is 1 to 6, preferably n is 1, 2, or3; wherein R² is hydrogen, C₁₋₁₂ alkyl, C₃₋₁₆ carbocyclyl or C₃₋₁₂heterocyclyl, C₁₋₁₂ alkylC₃₋₁₂ carbocyclyl, or C₁₋₁₂ alkylC₃₋₁₂heterocyclyl optionally substituted by one or more of C₁₋₆ alkyl,halogen, C₁₋₆ haloalkyl, —OR⁴, —SR⁴, —NO₂, CN, —NR⁴R⁴, —NR⁴COR⁴,—NR⁴CONR⁴R⁴, —NR⁴CO₂R⁴, —CO₂R⁴, —COR⁴, —CONR⁴ ₂, —SO₂R⁴, —SONR⁴ ₂,—SOR⁴, —SO₂NR⁴R⁴, —NR⁴SO₂R⁴, wherein the C₁₋₁₂ alkyl group optionallyincorporates on or two insertions selected for the group consisting of—O—, —N(R⁴)—, —S—, —SO—, —SO₂—, wherein each R⁴ may be the same ordifferent and is defined below; wherein two R² and NR² ₂ may form apartially saturated, unsaturated or fully saturated five to sevenmembered ring containing one to three heteroatoms, optionally andindependently substituted with one or more halogen, C₁₋₁₂ alkyl, C₂₋₁₂alkenyl, C₂₋₁₂ alkynyl, C₁₋₁₂ haloalkyl, C₃₋₁₂ carbocyclyl, C₃₋₁₂heterocyclyl, —OR⁵, —SR⁵, —NO₂, CN, —NR⁵R⁵, —NR⁵COR⁵, —NR⁵CONR⁵R⁵,—NR⁵CO₂R⁵, —CO₂R⁵, —COR⁵, —CONR⁵ ₂, —SO₂R⁵, —SONR⁵ ₂, —SOR⁵, —SO₂NR⁵R⁵,—NR⁵SO₂R⁵; and each saturated carbon in the optional ring is furtheroptionally and independently substituted by ═O, ═S, NNR⁶ ₂, ═N—OR⁶,═NNR⁶COR⁶, ═NNR⁶CO₂R⁶, ═NNSO₂R⁶, or ═NR⁶; wherein R³ is hydrogen, C₁₋₆alkyl, C₁₋₆ haloalkyl, or C₆₋₁₂ aryl; wherein R⁴ is hydrogen, C₁₋₆alkyl, C₁₋₆ haloalkyl, or C₆₋₁₂ aryl; wherein R⁵ is hydrogen, C₁₋₁₂alkyl, C₃₋₁₆ carbocyclyl or C₃₋₁₂ heterocyclyl, optionally substitutedby one or more of C₁₋₆ alkyl, halogen, C₁₋₆ haloalkyl, —OR⁷, —SR⁷, —NO₂,CN, —NR⁷R⁷, —NR⁷COR⁷, —NR⁷CONR⁷R⁷, —NR⁷CO₂R⁷, —CO₂R⁷, —COR⁷, —CONR⁷ ₂,—SO₂R⁷, —SONR⁷ ₂, —SOR⁷, —SO₂NR⁷R⁷, —NR⁷SO₂R⁷; wherein the C₁₋₁₂ alkylgroup optionally incorporates one or two insertions selected from thegroup consisting of —O—, —N(R⁷)—, —S—, —SO—, —SO₂—, wherein each R⁷ maybe the same or different and is defined below; wherein R⁶ is hydrogen,C₁₋₁₂ alkyl, C₃₋₁₆ carbocyclyl or C₃₋₁₂ heterocyclyl, optionallysubstituted by one or more of C₁₋₆ alkyl, halogen, C₁₋₆ haloalkyl, —OR⁷,—SR⁷, —NO₂, CN, —NR⁷R⁷, —NR⁷COR⁷, —NR⁷CONR⁷R⁷, —NR⁷CO₂R⁷, —CO₂R⁷, —COR⁷,—CONR⁷ ₂, —SO₂R, —SONR⁷ ₂, —SOR⁷, —SO₂NR⁷R⁷, —NR⁷SO₂R⁷; wherein theC₁₋₁₂ alkyl group optionally incorporates one or two insertions selectedfrom the group consisting of —O—, —N(R⁷)—, —S—, —SO—, —SO₂—, whereineach R⁷ may be the same or different and is defined below; wherein R⁷ ishydrogen, C₁₋₆ alkyl, or C₁₋₆ haloalkyl; wherein the optionallysubstituted carbocyclyl or heterocyclyl group in R1 and Z is optionallyand independently fused to a partially saturated, unsaturated or fullysaturated five to seven membered ring containing zero to threeheteroatoms, and each substitutable carbon atom in R1 or Z, includingthe optional fused ring, is optionally and independently substituted byone or more of halogen, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₁₋₁₂haloalkyl, C₃₋₁₂ carbocyclyl, C₃₋₁₂ heterocyclyl, —(CH₂)_(n)OR¹²,—(CH₂)_(n)NR¹² ₂, —OR¹², —SR¹², —NO₂, CN, —NR¹²R¹², —NR¹²COR¹²,—NR¹²CONR¹²R¹², —NR¹²CO₂R¹², —CO₂R¹², —COR¹², —CONR¹² ₂, —SO₂R¹²,—SONR¹² ₂, —SOR¹², —SO₂NR¹²R¹², —NR¹²SO₂R¹²; wherein the C₁₋₁₂ alkylgroup optionally contains one or more insertions selected from —O—,—N(R¹²)—, —S—, —SO—, —SO₂—, and each saturated carbon in the optionallyfused ring is further optionally and independently substituted by ═O,═S, NNR¹³ ₂, ═N—OR¹³, ═NNR¹³COR¹³, ═NNR¹³CO₂R¹³, ═NNSO₂R¹³, or ═NR¹³;and each substitutable nitrogen atom in R¹ is optionally substituted by—R¹⁴, —COR¹⁴, —SO₂R¹⁴, or —CO₂R¹⁴; wherein n is 1 to 6, preferably n is1, 2, or 3; wherein R¹² is hydrogen, C₁₋₁₂ alkyl, C₃₋₁₆ carbocyclyl orC₃₋₁₂ heterocyclyl, optionally substituted by one or more of C₁₋₆ alkyl,halogen, C₁₋₆ haloalkyl, —OR¹⁵, —SR¹⁵, —NO₂, CN, —NR¹⁵R¹⁵, —NR¹⁵COR¹⁵,—NR¹⁵CONR¹⁵R¹⁵, —NR¹⁵CO₂R¹⁵, —CO₂R¹⁵, —COR¹⁵, —CONR¹⁵ ₂, —SO₂R¹⁵,—SONR¹⁵ ₂, —SOR¹⁵, —SO₂NR¹⁵R¹⁵, —NR¹⁵SO₂R¹⁵; wherein the C₁₋₁₂ alkylgroup optionally incorporates one or two insertions selected from thegroup consisting of —O—, —N(R¹⁵)—, —S—, —SO—, —SO₂—, wherein each R⁷ maybe the same or different and is defined below; wherein two R¹² and NR¹²₂ may form a partially saturated, unsaturated or fully saturated five toseven membered ring containing one to three heteroatoms, optionally andindependently substituted with one or more halogen, C₁₋₁₂ alkyl, C₂₋₁₂alkenyl, C₂₋₁₂ alkynyl, C₁₋₁₂ haloalkyl, C₃₋₁₂ carbocyclyl, C₃₋₁₂heterocyclyl, —OR¹⁶, —SR¹⁶, —NO₂, CN, —NR¹⁶R¹⁶, —NR¹⁶COR¹⁶,—NR¹⁶CONR¹⁶R¹⁶, —NR¹⁶CO₂R¹⁶, —CO₂R¹⁶, —COR¹⁶, —CONR¹⁶ ₂, —SO₂R¹⁶,—SONR¹⁶ ₂, —SOR¹⁶, —SO₂NR¹⁶R¹⁶, —NR¹⁶SO₂R¹⁶; and each saturated carbonin the optional ring is further optionally and independently substitutedby ═O, ═S, NNR¹⁷ ₂, ═N—OR¹⁷, ═NNR¹⁷COR¹⁷, ═NNR¹⁷CO₂R¹⁷, ═NNSO₂R¹⁷, or═NR¹⁷; wherein R¹³ is hydrogen, C₁₋₁₂ alkyl, C₃₋₁₆ carbocyclyl or C₃₋₁₂heterocyclyl, optionally substituted by one or more of C₁₋₆ alkyl,halogen, C₁₋₆ haloalkyl, —OR¹⁵, —SR¹⁵, —NO₂, CN, —NR¹⁵R¹⁵, —NR¹⁵COR¹⁵,—NR¹⁵CONR¹⁵R¹⁵, —NR¹⁵CO₂R¹⁵, —CO₂R¹⁵, —COR¹⁵, —CONR¹⁵ ₂, —SO₂R¹⁵,—SONR¹⁵ ₂, —SOR¹⁵, —SO₂NR¹⁵R¹⁵, —NR¹⁵SO₂R¹⁵; wherein the C₁₋₁₂ alkylgroup optionally incorporates one or two insertions selected from thegroup consisting of —O—, —N(R¹⁵)—, —S—, —SO—, —SO₂—, wherein each R¹⁵may be the same or different and is defined below; wherein R¹⁴ ishydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, or C₆₋₁₂ aryl; wherein R¹⁵ ishydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl; wherein R¹⁶ is hydrogen, C₁₋₁₂alkyl, C₃₋₁₆ carbocyclyl or C₃₋₁₂ heterocyclyl, optionally substitutedby one or more of C₁₋₆ alkyl, halogen, C₁₋₆ haloalkyl, —OR¹⁸, —SR¹⁸,—NO₂, CN, —NR¹⁸R¹⁸, —NR¹⁸COR¹⁸, —NR¹⁸CONR¹⁸R¹⁸, —NR¹⁸CO₂R¹⁸, —CO₂R¹⁸,—COR¹⁸, —CONR¹⁸ ₂, —SO₂R¹⁸, —SONR¹⁸ ₂, —SOR¹⁸, —SO₂NR¹⁸R¹⁸, —NR¹⁸SO₂R¹⁸;wherein the C₁₋₁₂ alkyl group optionally incorporates one or twoinsertions selected from the group consisting of —O—, —N(R¹⁸)—, —S—,—SO—, —SO₂—, wherein each R¹⁸ may be the same or different and isdefined below; wherein R¹⁷ is hydrogen, C₁₋₁₂ alkyl, C₃₋₁₆ carbocyclylor C₃₋₁₂ heterocyclyl, optionally substituted by one or more of C₁₋₆alkyl, halogen, C₁₋₆ haloalkyl, —OR¹⁸, —SR¹⁸, —NO₂, CN, —NR¹⁸R¹⁸,—NR¹⁸COR¹⁸, —NR¹⁸CONR¹⁸R¹⁸, —NR¹⁸CO₂R¹⁸, —CO₂R¹⁸, —COR¹⁸, —CONR¹⁸ ₂,—SO₂R¹⁸, —SONR¹⁸ ₂, —SOR¹⁸, —SO₂NR¹⁸R¹⁸, —NR¹⁸SO₂R¹⁸; wherein the C₁₋₁₂alkyl group optionally incorporates one or two insertions selected fromthe group consisting of —O—, —N(R¹⁸)—, —S—, —SO—, —SO₂—, wherein eachR¹⁸ may be the same or different and is defined below; wherein R¹⁸ ishydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl. These compounds have beendescribed in International Publication Number WO 2004/101565 and all ofwhich or any present or future corresponding U.S. application or patentare hereby incorporated by reference. Preferred embodiments include:

The following derivatives are contemplated for use as therapeutics intreating type I diabetes:

wherein ring A is an optionally substituted benzene ring, X is —O—, —N═,—NR³— or —CHR³—, R² is an acyl group, an optionally esterified orthioesterified carboxyl group, and optionally substituted carbamoylgroup or an optionally substituted amino group and the line, a brokenline shows a single bond or a double bond, and R¹ is a hydrogen atom,optionally substituted hydrocarbon group, and optionally substitutedheterocyclic group and the like. These compounds have been described inJapanese Publication JP2004210772 and all of which or any present orfuture corresponding U.S. application or patent are hereby incorporatedby reference. Preferred embodiments include:

Further illustrative examples can be found in the identified reference.

The following derivatives are contemplated for use as therapeutics intreating type I diabetes:

wherein each of Ar^(a) and Ar^(b) is an aromatic group optionally havingsubstituents, Ar^(a) and Ar^(b) optionally form a condensed cyclic grouptogether with the adjacent carbon atom; ring B^(a) is anitrogen-containing heterocycle optionally having substituents; X^(a)and Y^(a) are the same or different and each is (1) a bond, (2) anoxygen atom, (3) S(O)_(p) (wherein p is an integer of 0 to 2), (4)NR^(d) (wherein R^(d) is a hydrogen atom or a lower alkyl group) or (5)a divalent linear lower hydrocarbon group optionally having substituentsand containing 1 to 3 hetero atom(s); ring A^(a) is a 5-membered ringoptionally having substituents; R^(a) and R^(b) are the same ordifferent and each is (1) a hydrogen atom, (2) a halogen atom, (3) ahydrocarbon group optionally having substituents, (4) an acyl group or(5) a hydroxy group optionally having a substituent; R^(c) is (1) ahydrogen atom, (2) a hydroxy group optionally substituted by a loweralkyl group or (3) a carboxyl group. These compounds have been describedin U.S. Patent Application Publication 2004/0254189 and JapanesePublication JP2004161716, all of which or any present or futurecorresponding U.S. application or patent are hereby incorporated byreference. Preferred embodiments include:

Further illustrative embodiments can be found in the correspondingidentified references.

The following derivatives are contemplated for use as therapeutics intreating type I diabetes:

These compounds have been described in Japanese Publication JP2003015481and all of which or any present or future corresponding U.S. applicationor patent are hereby incorporated by reference.

The following derivatives are contemplated for use as therapeutics intreating type I diabetes:

wherein Y is selected from O, NH, N(R), S, S(O) or S(O)₂; X is selectedfrom O, NH or N(R); R¹ and R² are each independently selected from H, aC₁-C₆ straight chain or branched alkyl or alkenyl group, optionallysubstituted with one to four substituents, each of which isindependently selected from NH₂, NHR, N(R)₂, NO₂, OH, OR, CF₃, halo, CN,CO₂H, CONH₂, CONHR, CON(R)₂, COR, SR, S(O)R, S(O)₂R, S(O)2NH₂, S(O)₂NHRor R; a 5-7 membered aromatic or non-aromatic carbocyclic orheterocyclic ring, optionally substituted with one to four substituents,each of which is independently selected from NH₂, NHR, N(R)₂, NO₂, OH,OR, CF₃, halo, CN, CO₂H, CONH₂, CONHR, CON(R)₂, COR, SR, S(O)R, S(O)₂R,S(O)₂NH₂, S(O)₂NHR or R; or a 9-10 membered bicyclic aromatic ornon-aromatic carbocyclic or heterocyclic ring optionally substitutedwith one to four substituents, each of which is independently selectedfrom NH₂, NHR, N(R)₂, NO₂, OH, OR, CF₃, halo, CN, CO₂H, CONH₂, CONHR,CON(R)₂, COR, SR, S(O)R, S(O)₂R, S(O)₂NH₂, S(O)₂NHR or R; wherein saidheterocyclic ring contains 1 to 4 heteroatoms, each of which heteroatomsare independently selected from N, O, S, SO or SO₂; and R is selectedfrom a C₁-C₆ straight chain or branched alkyl or alkenyl group, a 5-7membered aromatic or non-aromatic carbocyclic or heterocyclic ring, or a9-10 membered bicyclic aromatic or non-aromatic carbocyclic orheterocyclic ring system. These compounds have been described in U.S.Patent Application Publication 2003/100549 and all of which or anypresent or future corresponding U.S. application or patent are herebyincorporated by reference. Preferred embodiments include:

Further illustrative embodiment can be found in the correspondingidentified reference.

The following derivatives are contemplated for use as therapeutics intreating type I diabetes:

wherein ring A and ring B are each an optionally substituted benzenering, X is —O—, —N═, —NR³— or —CHR³—, R² is an acyl group, an optionallyesterified or thioesterified carboxyl group, and optionally substitutedcarbamoyl group or an optionally substituted amino group and the line, abroken line shows a single bond or a double bond, and R¹ is a hydrogenatom, optionally substituted hydrocarbon group, and optionallysubstituted heterocyclic group and the like. These compounds have beendescribed in International Publication Number WO 2003/068750 and all ofwhich or any present or future corresponding U.S. application or patentare hereby incorporated by reference. Preferred embodiments include:

-   2-(benzo[1,3]dioxol-5-ylmethyl)-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic    acid methyl ester;-   6-bromo-1-oxo-4-phenyl-2-(4-sulfamoylbenzyl)-1,2-dihydroisoquinoline-3-carboxylic    acid methyl ester;-   6-bromo-2-(4-methanesulfonylbenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic    acid methyl ester;-   6-bromo-2-(4-carboxylbenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic    acid methyl ester;-   2-(2-acetylpiperidin-4-ylmethyl)-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic    acid methyl ester;-   6-bromo-2-[4-(3-carboxylpropionylamino)benzyl]-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic    acid methyl ester;-   6-bromo-1-oxo-4-phenyl-2-[4-(2-(pyrrolidini-1-yl)ethylcarbamoyl)benzyl]-1,2-dihydroisoquinoline-3-carboxylic    acid methyl ester;-   6-amino-2-(benzo[1,3]dioxol-5-ylmethyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic    acid methyl ester;-   6-bromo-2-(4-methanesulfonylbenzyl)-4-phenyl-3-propionyl-2H-isoquinolin-1-one;-   6-bromo-2-[4-(N′,N′-diethylhydrazinocarbonyl)benzyl]-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic    acid methyl ester;-   3-acetyl-6-bromo-4-phenyl-2-(4-sulfamoylbenzyl)-2H-isoquinolin-1-one;-   4-(6-chloro-3-butyryl-1-oxo-4-phenyl-1H-isoquinolin-2-ylmethyl)benzenesulfonamide;-   4-(6-bromo-1-oxo-4-phenyl-3-propionyl-1H-isoquinolin-2-ylmethyl)benzoic    acid;-   4-(6-chloro-1-oxo-4-phenyl-3-propionyl-1H-isoquinolin-2-ylmethyl)benzoic    acid;-   6-bromo-4-phenyl-3-propionyl-2-[4-(1H-tetrazol-5-yl)benzyl]-2H-isoquinolin-1-one;    and-   3-[(2Z)-3-aminobut-2-enoyl]-6-bromo-2-(4-methanesulfonylbenzyl)-4-phenyl-2H-isoquinolin-1-one.    Further illustrative embodiments can be found in the identified    reference(s).

The following derivatives are contemplated for use as therapeutics intreating type I diabetes:

wherein X is O, S or NR⁰, with R⁰ being H or an unsubstituted orsubstituted C₁-C₆ alkyl; G is an unsubstituted or substitutedpyrimidinyl group; R¹ is selected from the group comprising orconsisting of hydrogen, unsubstituted or substituted C₁-C₆-alkoxy,unsubstituted or substituted C₁-C₆-thioalkoxy, unsubstituted orsubstituted C₁-C₆-alkyl, unsubstituted or substituted C₂-C₆-alkenylunsubstituted or substituted C₂-C₆-alkynyl, primary, secondary ortertiary amino groups, aminoacyl, aminocarbonyl, unsubstituted orsubstituted C₁-C₆ alkoxycarbonyl unsubstituted or substituted aryl,unsubstituted or substituted heteroaryl, carboxyl, cyano, halogen,hydroxy, nitro, sulfoxy, sulfonyl sulfonamide, unsubstituted orsubstituted hydrazides; R² is selected from the group comprising orconsisting of hydrogen, unsubstituted or substituted C₁-C₆-alkyl,unsubstituted or substituted C₂-C₆-alkenyl, unsubstituted or substitutedC₂-C₆-alkynyl, unsubstituted or substituted C₁-C₆-alkyl-aryl,unsubstituted or substituted aryl or heteroaryl unsubstituted orsubstituted C₁-C₆-alkyl-heteroaryl, —C(O)—OR³, —C(O)—R³,—C(O)—NR³R^(3′), —(SO₂)R³, with R³ and R^(3′) being independentlyselected from the group comprising or consisting of hydrogen,unsubstituted or substituted C₁-C₆ alkyl, unsubstituted or substitutedC₂-C₆ alkenyl, unsubstituted or substituted C₂-C₆ alknyl, unsubstitutedor substituted aryl, unsubstituted or substituted heteroaryl,unsubstituted or substituted C₁-C₆-alkyl aryl, unsubstituted orsubstituted C₁-C₆-alkyl heteroaryl. These compounds have been describedin U.S. Patent Application Publication 2003/0162794 and all of which orany present or future corresponding U.S. application or patent arehereby incorporated by reference. Preferred embodiments include:

-   1,3-benzothiazol-2-yl(2-chloro-4-pyrimidinyl)-acetonitrile;-   1,3-benzothiazol-2-yl[2-methylsulfanyl)-4-pyrimidinyl]acetonitrile;-   1,3-benzothiazol-2-yl(2-{[2-(1H-imidazolyl-4-yl)ethyl-1]amino}-4-pyrimidinyl)acetonitrile;-   1,3-benzothiazol-2-yl[2-(methylamino)-4-pyrimidinyl]acetonitrile;-   1,3-benzothiazol-2-yl    {2-[(2-hydroxyethyl)amino]-4-pyrimidinyl}acetonitrile;-   1,3-benzothiazol-2-yl[2-(benzyloxy)pyrimidin-4-yl]acetonitrile;-   1,3-benzothiazol-2-yl[2-(4-methoxyphenoxy)pyrimidin-4-yl]acetonitrile;    and-   1,3-benzothiazol-2-yl(2-methoxy-4-pyrimidinyl)-acetonitrile. Further    illustrative embodiments can be found in the identified reference.

The following derivatives are contemplated for use as therapeutics intreating type I diabetes:

wherein Y is selected from —(CH₂)-Q¹; —(CO)-Q¹; —(CO)NH-Q¹; —(CO)—O-Q¹;—(SO₂)-Q¹ or —(SO₂)NH-Q¹; Q¹ is a C₁-C₆ straight chain or branched alkylor alkenyl group; a 5-7 membered aromatic or non-aromatic carbocyclic orheterocyclic ring; or a 9-14 membered bicyclic or tricyclic aromatic ornon-aromatic carbocyclic or heterocyclic ring system, wherein saidalkyl, alkenyl, ring or ring system is optionally substituted with oneto four substituents, each of which is independently selected from NH₂,NH—R, N(R)₂, NO₂, OH, OR, CF₃, halo, CN, CO₂H, C(O)—NH₂, C(O)—NH—R,C(O)—N(R)₂, C(O)—R, SR, S(O)—R, S(O)₂—R, S(O)₂—NH—R or —R; W is N or C;wherein when W is N, R⁸ is a lone pair of electrons; and wherein when Wis C, R⁸ is R⁷. A¹ is N or CR¹; A² is N or CR²; A³ is N or CR³; A⁴ is Nor CR⁴; provided that at least one of A¹, A², A³ and A⁴ must not be N;R¹ is —NHR⁵, —OR⁵, —SR⁵, or —R⁵; R², R³, and R⁴ are independentlyselected from —(CO)NH₂, —(CO)NHR, —(CO)N(R)₂, —NHR⁵, —NHCH₂R⁵, —OR⁵,—SR⁵, —R⁵, —NH(CO)—R⁶, —NH(CO)—NHR⁶, —NH(CO)—NH(CO)R⁶, —NH(CO)—OR⁶,—NH(SO₂)—R⁶, —NH(SO₂)—NHR⁶, —C(O)OH, —C(O)OR, —(CO)-Q¹, —(CO)NH-Q¹,—(CO)NR-Q¹, —(CO)—O-Q¹, —(SO₂)-Q¹ or —(SO₂)NH-Q¹; R⁵ and R⁶ are eachindependently selected from H; N(R)₂, NHOH, NO₂, C(O)OR or halo; a C₁-C₆straight chain or branched alkyl, alkenyl or alkynyl group; a 5-7membered aromatic or non-aromatic carbocyclic or heterocyclic ring; or a9-14 membered bicyclic or tricyclic aromatic or non-aromatic carbocyclicor heterocyclic ring; wherein said alkyl, alkenyl, ring or ring systemis optionally substituted with one to four substituents, each of whichis independently selected from NH₂, NHR, NHC(O)OR, N(R)₂, NO₂, OH, OR,CF₃, halo, CN, Si(R)₃, CO₂H, COOR, CONH₂, CONHR, CON(R)₂, COR, SR,S(O)R, S(O)₂R, S(O)₂NHR or R; R⁷ is H; a C₁-C₆ straight chain orbranched alkyl or alkenyl group; a 5-7 membered aromatic or non-aromaticcarbocyclic or heterocyclic ring; or a 9-14 membered bicyclic ortricyclic aromatic or non-aromatic carbocyclic or heterocyclic ring;wherein said alkyl, alkenyl, ring or ring system is optionallysubstituted with one to four substituents, each of which isindependently selected from NH₂, NHR, N(R)₂, NO₂, OH, OR, CF₃, halo, CN,CO₂H, CONH₂, CONHR, CON(R)₂, COR, SR, S(O)R, S(O)₂R, S(O)₂NHR or R; R isa C₁-C₆ straight chain or branched alkyl or alkenyl group, a 5-7membered aromatic or non-aromatic carbocyclic or heterocyclic ring, or a9-10 membered bicyclic aromatic or non-aromatic carbocyclic orheterocyclic ring system; and Z is CH or N. These compounds have beendescribed in U.S. Patent Application Publication 2003/0162794 and all ofwhich or any present or future corresponding U.S. application or patentare hereby incorporated by reference. Preferred embodiments include:

Further illustrative embodiments can be located in the identifiedreference.

The following derivatives are contemplated for use as therapeutics intreating type I diabetes:

wherein: R¹ is aryl or heteroaryl, each of which is optionallysubstituted with one or more of R³, OR³, OCOR³, COOR³, COR³, CON⁴R³R⁴,NHCOR³, NR³R⁴, NHSO₂R³, SO₂R³, SO₂NR³R⁴, SR³, CN, halogeno and NO₂; R²is R⁵, R⁶, COR⁵, COR⁵, CONHR⁵, CONHR⁶, CON(R⁶)₂, COOR⁵, COOR⁶, SO₂R⁵ orSO₂R⁶; R3 and R4 are each independently hydrogen, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, (C₃₋₈ cycloalkyl) C₁₋₆ alkyl,heterocycle, heterocycle C₁₋₆ alkyl, C₁₋₆ fluoroalkyl, C₁₋₆trifluoroalkoxyl; R⁵ is aryl or heteroaryl, each of which is optionallysubstituted with one or more of R⁷, OR⁷, OCOR⁷, COOR⁷, COR⁷, CONR⁷R⁸,CONHOR⁷, NHCOR⁷, NR⁷R⁸, NHSO₂R⁷, SO₂R⁷, SO₂NHR⁷R⁸, SR⁷, R⁷SR⁸, CN,halogeno, oxygen and NO₂; R⁶ is hydrogen, C₁₋₆ alkyl, C₃₋₈ cycloalkyl,(C₃₋₈ cycloalkyl) C₁₋₆ alkyl, heterocycle, heterocycle C₁₋₆ alkyl,heteroaryl C₁₋₆ alkyl; aryl C₁₋₆ alkyl, C₁₋₆ alkoxyl, or C₂₋₆ alkenyl,wherein any of C₁₋₆ alkyl, C₃₋₈ cycloalkyl, (C₃₋₈ cyclolakyl) C₁₋₆alkyl, heterocycle, heerocycle C₁₋₆ alkyl, heteronaryl C₁₋₆ alkyl, arylC₁₋₆ alkyl, C₁₋₆ alkoxyl and C₂₋₆ alkenyl is optionally substituted withone or more A; R⁷ and R⁸ are each independently hydrogen, C₁₋₆ alkyl,C₃₋₈ cycloalkyl, (C₃₋₈ cycloalkyl) C₁₋₆ alkyl, C₂₋₆ alkenyl, aryl,heteroaryl, heteroaryl C₁₋₆ alkyl, heterocycle, heterocycle C₁₋₆ alkyl,aryl, C₁₋₆ fluoroalkyl and Cl₆ chloroalkyl, wherein any of C₁₋₆ alkyl,C₃₋₈ cycloalkyl, (C₃₋₈ cycloalkyl) C₁₋₆ alkyl, C₂₋₆ alkenyl, heteroaryl,heteroaryl C₁₋₆ alkyl, heterocycle and heterocycle C₁₋₆ alkyl isoptionally substituted with one or more B; R⁹ and R¹⁰ are eachindependently hydrogen, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, (C₃₋₈ cycloalkyl)C₁₋₆ alkyl, C₂₋₆ alkenyl, heterocycle, heterocycle C₁₋₆ alkyl,heteroaryl, heteroaryl C₁₋₆ alkyl, aryl or aryl C₁₋₆ alkyl, wherein anyof C₁₋₆ alkyl, C₃₋₈ cycloalkyl, (C₃₋₈ cycloalkyl) C₁₋₆ alkyl, C₂₋₆alkenyl, heterocycle, heterocycle C₁₋₆ alkyl, heteroaryl, heteroarylC₁₋₆ alkyl, aryl or aryl C₁₋₆ alkyl is optionally substituted with oneor more B; A is R⁹, OR⁹, OCOR⁹, COOR⁹, COR⁹, CONR⁹R¹⁰, CONHOR⁹, NHCOR⁹,NR⁹R¹⁰, NR⁹SO₂R¹⁰, SO₂R⁹, SO₂NR⁹R¹⁰, SR⁹, R⁹SR¹⁰, CN or halogen; B isC₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino, di (C₁₋₆ alkyl)amino orhalogen. These compounds have been described in InternationalPublication Number WO 2004/101565 and all of which or any present orfuture corresponding U.S. application or patent are hereby incorporatedby reference. Preferred embodiments include:

-   N,N′-Bis[4-(trifluoromethyl)phenyl]-4,4′-bipyridine-2,2′-diamine;-   N,N′-Bis(4-fluorophenyl)-4,4′-bipyridine-2,2′-diamine;-   N,N′-Bis(3,4-difluorophenyl)-4,4′-bipyridine-2,2′-diamine;-   N,N′-Bis[3-(trifluoromethyl)phenyl]-4,4′-bipyridine-2,2′-diamine;-   N,N′-Bis[3-(trifluoromethyl)phenyl]-4,4′-bipyridine-2,2′-diamine;-   N,N′-Bis(2-fluorophenyl)-4,4′-bipyridine-2,2′-diamine;N,N′-Bis(2-methylphenyl)-4,4′-bipyridine-2,2′-diamine;N,N′-Bis(2-aminophenyl)-4,4′-bipyridine-2,2′-diamine;N,N′-Bis(2-methoxyphenyl)-4,4′-bipyridine-2,2′-diamine;-   N,N′-Bis(2-ethoxyphenyl)-4,4′-bipyridine-2,2′-diamine;-   N-(2′-anilino-4,4-bipyridin-2-yl)trans-4-methoxycyclohexanecarboxamide;-   N    (2′-anilino-4,4′-bipyridin-2-yl)-cis-4-methoxycyclohexanecarboxamide;-   N-12′-[(4-fluorophenyl)amino]-4,4′-bipyridin-2-yl}-trans-4-methoxycyclohexanecarboxamide;-   N-{2′-[(4-fluorophenyl)amino]-4,4′-bipyridin-2-yl}-cis-4-methoxycyclohexanecarboxamide;-   N-(6-methylpyridin-2-yl)-N-phenyl-4,4′-bipyridine-2,2′-diamine;    N-phenyl-N-pyridin-2-yl-4,4′-bipyridine-2,2′-diamine;-   {4-[(4-methylpiperazin-1-yl)    sulfonyl]phenyl}-N-phenyl-4,4′-bipyridine-2,2′-diamine;-   N-phenyl-N′-pyridin-3-yl-4,4′-bipyridine-2,2′-diamine;-   N-phenyl-N′-pyrimidin-2-yl-4,4′-bipyridine-2,2′-diamine;-   N-phenyl-N′-pyrimidin-5-yl-4,4′-bipyridine-2,2′-diamine;-   (2E)-1-{4-[(2′-anilino-4,4′-bipyridin-2-yl)amino]phenyl}-3-(dimethylamino)    prop-2-en-1-one;-   4-[(2′-anilino-4,4′-bipyridin-2-yl)amino]-N-(2-pyrrolidin-1-ylethyl)benzenesulfonamide;-   4-[(2′-anilino-4,4′-bipyridin-2-yl)amino]-N-(2-morpholin-4-ylethyl)benzenesulfonamide;-   N-{4-[(4-ethylpiperazin-1-yl)    sulfonyl]phenyl}-N′-phenyl-4,4′-bipyridine-2,2′-diamine;-   N-phenyl-N′-pyridin-4-yl-4,4′-bipyridine-2,2′-diamine;-   N-(2′-anilino-4,4′-bipyridin-2-yl)tetrahydrofuran-3-carboxamide;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-3-piperidin-1-ylpropanamide;-   N-(2′-anilino-4,4′-bipyridin-2-yl)tetrahydrofuran-3-carboxamide;-   N-(2′-anilino-4,4′-bipyridin-2-yl)nicotinamide;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-4-(dimethylamino)benzamide;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-2,6-dimethoxynicotinamide;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-1H-indole-2-carboxamide;-   N-(2′-anilino-4,4′-bipyridin-2-yl)pyridine-2-carboxamide;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-3-furamide;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-1,2,3-thiadiazole-4-carboxamide;-   N-(2′-anilino-4,4′-bipyridin-2-yl) isoxazole-5-carboxamide;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-5-methylisoxazole-3-carboxamide;-   N-(2′-anilino-4,4′-bipyridin-2-yl)pyrazine-2-carboxamide;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-1-methyl-1H-imidazole-4-carboxamide;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-2-furamide;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-4-methoxybenzamide;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-5-bromo-2-furamide;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-2-(methylthio) nicotinamide;-   Methyl-4-{[(2′-anilino-4,4′-bipyridin-2-yl)amino]carbonyl}benzoate;-   3-(acetylamino)-N-(2′-anilino-4,4′-bipyridin-2-yl)benzamide;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-4-oxo-4,5,6,7-tetrahydro-1-benzofuran-3-carboxamide;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-5-[(pyridin-2-ylthio)    methyl]-2-furamide;-   N-(2′-anilino-4,4′-bipyridin-2-yl)nicotinamide 1-oxide;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-3-hydroxypyridine-2-carboxamide;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-6-bromopyridine-2-carboxamide;-   N-(2′-anilino-4,4′-bipyridin-2-yl)isonicotinamide 1-oxide;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-2-hydroxynicotinamide;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-6-hydroxypyridine-2-carboxamide;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-3-benzoylpyridine-2-carboxamide;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-6-methylpyridine-2-carboxamide;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-3,5-dimethylisoxazole-4-carboxamide;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-2-methoxynicotinamide;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-4-methyl-1,2,3-thiadiazole-5-carboxamide;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-2-chloroisonicotinamide;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-5-methylisoxazole-4-carboxamide;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-3-methylisoxazole-4-carboxamide;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-1-methyl-1H-pyrrole-2-carboxamide;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-2-chloronicotinamide;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-5-chloro-1H-indole-2-carboxamide;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-4-chloro-1H-pyrazole-3-carboxamide;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-5-methyl-1H-pyrazole-3-carboxamide;-   (2E)-N-(2′-anilino-4,4′-bipyridin-2-yl)-3-(3-furyl)acrylamide;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-3-(2-oxo-1,3-benzoxazol-3(2H)-yl)    propanamide;-   N′-(2′-anilino-4,4′-bipyridin-2-yl)-N,N-dimethylsuccinamide;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-2-[(4-chlorophenyl)    sulfonyl]acetamide;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-5-oxoprolinamide;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-3-methoxypropanamide;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-4-methoxycyclohexanecarboxamide;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-3-methoxypropanamide;-   N-(2′-anilino-4,4′-bipyridin-2-yl)tetrahydrofuran-3-carboxamide;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-4-(dimethylamino) butanamide;-   N-(2′-anilino-4,4′-bipyridin-2-yl)nicotinamide;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-4-(dimethylamino)benzamide;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-2,6-dimethoxynicotinamide;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-1H-indole-2-carboxamide;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-5-methylpyrazine-2-carboxamide;-   N-(2′-anilino-4,4′-bipyridin-2-yl)pyridine-2-carboxamide;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-3-furamide;N    (2′-anilino-4,4′-bipyridin-2-yl)-N-phenylurea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-phenylurea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-[1-(4-bromophenyl)ethyl]urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-thien-3-ylurea;N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-(2-methylphenyl)urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-(4-methylphenyl)urea;N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-(3-fluorophenyl)urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-(2-fluorophenyl)urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-(4-fluorophenyl)urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-[4-(chloromethyl)phenyl]urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-(3-cyanophenyl)urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-(4-cyanophenyl)urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-(2-cyanophenyl)urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-(2,3-dimethylphenyl)urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-(2,5-dimethylphenyl)urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-(4-ethylphenyl)urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-(3-ethylphenyl)urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-(4-methoxyphenyl)urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-(3-methoxyphenyl)urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-(2-methoxyphenyl)urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-(5-fluoro-2-methylphenyl)urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-(2-fluorobenzyl)urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-(2-fluoro-5-methylphenyl)urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-(3-fluorobenzyl)urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-(2-chlorophenyl)urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-(3-chlorophenyl)urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-(2-chlorobenzyl)urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-(2,5-difluorophenyl)urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-(2,4-difluorophenyl)urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-(3,4-dichlorobenzyl)urea;-   N-(4-acetylphenyl)-N′-(2′-anilino-4,4′-bipyridin-2-yl)urea;-   N-(3-acetylphenyl)-N′-(2′-anilino-4,4′-bipyridin-2-yl)urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-(4-isopropylphenyl)urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-(2-isopropylphenyl)urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-(2-ethyl-6-methylphenyl)urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-mesitylurea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-(2-propylphenyl)urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-[4-(dimethylamino)    phenyl]urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-1,3-benzodioxol-5-ylurea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-(4-methoxy-2-methylphenyl)urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-(2-methoxy-5-methylphenyl)urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-(4-ethoxyphenyl)urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-(4-methoxybenzyl)urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-(4-nitrophenyl)urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-(3-nitrophenyl)urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-[3-(methylthio) phenyl]urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-[4-(methylthio) phenyl]urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-(2-methylbenzyl)urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-(5-chloro-2-methylphenyl)urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-(2-chloro-5-methylphenyl)urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-(2-chlorobenzyl)urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-(3-chloro-4-fluorophenyl)urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-(2,3,4-trifluorophenyl)urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-(4-butylphenyl)urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-(2-isopropyl-6-methylphenyl)urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-(2-tert-butylphenyl)urea;-   methyl    4-({[(2′-anilino-4,4′-bipyridin-2-yl)amino]carbonyl}amino)benzoate;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-(3,4-dimethoxyphenyl)urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-(3,5-dimethoxyphenyl)urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-(3-chloro-4-methoxyphenyl)urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-[4-(difluoromethoxy)phenyl]urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-[2-(trifluoromethyl)phenyl]urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-[3-(trifluoromethyl)phenyl]urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-[4-(trifluoromethyl)phenyl]urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-(2,5-dichlorophenyl)urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-(3,5-dichlorophenyl)urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-(3,4-dichlorophenyl)urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-(2,3-dichlorophenyl)urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-(2,4-dichlorophenyl)urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-(4-bromo-3-methylphenyl)urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-(2,6-dichloropyridin-4-yl)urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-(4-butyl-2-methylphenyl)urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-[5-methyl-2-(trifluoromethyl)-3-furyl]urea;-   ethyl3-({[(2′-anilino-4,4′-bipyridin-2-yl)amino]carbonyl}amino)benzoate;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-(4-butoxyphenyl)urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-(2,6-diisopropylphenyl)urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-(4-methylbenzyl)urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-(5-chloro-2,4-dimethoxyphenyl)urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-{4-[(trifluoromethyl)thio]phenyl}urea;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-N′-[3,5-bis(trifluoromethyl)phenyl]urea;-   1-acetyl-N-(2′-anilino-4,4′-bipyridin-2-yl)piperidine-4-carboxamide;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-5-oxoprolinamide;-   N3-acetyl-N1-(2′-anilino-4,4′-bipyridin-2-yl)-1-alaninamide;-   N-(2′-anilino-4,4′-bipyridin-2-yl)piperidine-4-carboxamide;-   3-amino-N-(2′-anilino-4,4′-bipyridin-2-yl) butanamide;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-L-prolinamide;-   N-(2′-anilino-4,4′-bipyridin-2-yl)acetamide;-   Methyl 2′-anilino-4,4′-bipyridin-2-ylcarbamate;-   N-(2′-anilino-4,4′-bipyridin-2-yl)methanesulfonamide;-   N-(2′-anilino-4,4′-bipyridin-2-yl)cyclohexanecarboxamide;-   1-Acetyl-N-(2′-anilino-4,4′-bipyridin-2-yl)piperidine-2-carboxamide;-   1-Acetyl-N-(2′-anilino-4,4′-bipyridin-2-yl)piperidine-3-carboxamide;-   Ethyl-4-[(2′-anilino-4,4′-bipyridin-2-yl)amino]-4-oxobutanoate;-   N-(2′-anilino-4,4′-bipyridin-2-yl)tetrahydrofuran-2-carboxamide;-   (S)-3 N2-acetyl-N1-(2′-anilino-4,4′-bipyridin-2-yl)methioninamide;-   N-(2′-anilino-4,4′-bipyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide;-   Ethyl 3-[(2′-anilino-4,4′-bipyridin-2-yl)amino]-3-oxopropanoate;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-3-(methylthio) propanamide;-   N-(2′-anilino-4,4′-bipyridin-2-yl)-2-pyrrolidin-2-ylacetamide;-   (3S)-3-amino-N (2′-anilino-4,4′-bipyridin-2-yl)-4-cyanobutanamide;-   N1-(2′-anilino-4,4′-bipyridin-2-yl)cyclopropane-1,1-dicarboxamide;-   (3S)-1-acetyl-N-(2′-anilino-4,4′-bipyridin-2-yl)piperidine-3-carboxamide;-   N-(2′-anilino-4,4′-bipyridin-2-yl)tetrahydrofuran-3-carboxamide (+)    and (−);-   N{2′-[(4-fluorophenyl)amino]-4,4′-bipyridin-2-yl}tetrahydrofuran-3-carboxamide;-   N{2′-[(4-fluorophenyl)amino]-4,4′-bipyridin-2-yl}tetrahydro-2H-pyran-4-carboxamide;-   Ethyl4-({2′-[(4-fluorophenyl)amino]-4,4′-bipyridin-2-yl}amino)-4-oxobutanoate;    4-({2′-(4-Fluorophenyl)amino]-4,4′-bipyridin-2-yl}amino)-4-oxobutanoic    acid;-   N-2′-[(4-fluorophenyl)amino]-4,4′-bipyridin-2-yl}-3-(methylthio)    propanamide;-   (f)-1-Acetyl-N    {2′-[(4-fluorophenyl)amino]-4,4′-bipyridin-2-yl}piperidine-3-carboxamide;-   (3R)-1-Acetyl-N-{2′-[(4-fluorophenyl)amino]-4,4′-bipyridin-2-yl}piperidine-3-carboxamide;-   (3R)-1-acetyl-N-{2′-[(4-fluorophenyl)amino]-4,4′-bipyridin-2-yl}piperidine-3-carboxamide;-   1-Acetyl-N    {2′-[(4-fluorophenyl)amino]-4,4′-bipyridin-2-yl}pyrrolidine-3-carboxamide;-   3-(Aminosulfonyl)-N    {2′-[(4-fluorophenyl)amino]-4,4′-bipyridin-2-yl}benzamide;-   Ethyl2-{[(2′-anilino-4,4′-bipyridin-2-yl)amino]methyl}cyclopropanecarboxylate;-   2-{[(2′-Anilino-4,4′-bipyridin-2-yl)amino]methyl}cyclopropanecarboxylic    acid;-   N-phenyl-N-(tetrahydro-2H-pyran-4-ylmethyl)-4,4′-bipyridine-2,2′-diamine;-   N-phenyl-N-(tetrahydrofuran-3-ylmethyl)-4,4′-bipyridine-2,2′-diamine.

The following derivatives are contemplated for use as therapeutics intreating type I diabetes:

wherein: R¹ is selected from hydrogen, CONH₂, T_((n))-R, or T_((n))-Ar¹;R is an aliphatic or substituted aliphatic group; n is zero or one; T isC(═O), CO₂, CONH, S(O)₂, S(O)₂NH, COCH₂ or CH₂; R₂ is selected fromhydrogen, —R, —CH₂OR, —CH₂OH, —CH═O, —CH₂SR, —CH₂S(O)₂R, —CH₂(C═O)R,—CH₂CO₂R, —CH₂CO₂H, —CH₂CN, —CH₂NHR, —CH₂N(R)₂, —CH═N—OR, —CH═NNHR,—CH═NN(R)₂, —CH═NNHCOR, —CH═NNHCO₂R, —CH═NNHSO₂R, -aryl, —CH₂(aryl),—CH₂NH₂, —CH₂NHCOR, —CH₂NHCONHR, —CH₂NHCON(R)₂, —CH₂NRCOR, —CH₂NHCO₂R,—CH₂CONHR, —CH₂CON(R)₂, —CH₂SO₂NH₂, —CH₂(heterocyclyl), or—(heterocyclyl); R³ is selected from hydrogen, —R, hydroxyalkyl,alkoxyalkyl, alkylthioalkyl, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, oraryloxyalkyl; G is hydrogen or C₁₋₃ alkyl; Q-NH is

wherein the H of Q-NH is optionally replaced by R, COR, S(O)₂R, or CO₂R;A is N or CH; Ar¹ is aryl, substituted aryl, heterocyclyl or substitutedheterocyclyl, wherein Ar¹ is optionally fused to a partially unsaturatedor fully unsaturated five to seven membered ring containing zero tothree heteroatoms; wherein each substitutable carbon atom in Ar¹,including the fused ring when present, is optionally and independentlysubstituted by halo, R, OR, SR, OH, NO₂, CN, NH₂, NHR, N(R)₂, NHCOR,NHCONHR, NHCON(R)₂, NRCOR, NHCO₂R, CO₂R, CO₂H, COR, CONHR, CON(R)₂,S(O)₂R, SONH₂, S(O)R, SO₂NHR, or NHS(O)₂R, and wherein each saturatedcarbon in the fused ring is further optionally and independentlysubstituted by ═O, ═S, ═NNHR, ═NNR₂, ═N—OR, ═NNHCOR, ═NNHCO₂R, ═NNHSO₂R,or ═NR; and wherein each substitutable nitrogen atom in Ar¹ isoptionally substituted by R, COR, S(O)₂R, or CO₂R. These compounds havebeen described in U.S. Patent Application Publication 2002/0111353 andall of which or any present or future corresponding U.S. application orpatent are hereby incorporated by reference. Preferred embodimentsinclude:

Further illustrative embodiments can be found in the correspondingidentified reference.

The following derivatives are contemplated for use as therapeutics intreating type I diabetes:

wherein: X—Y—Z is selected from one of the following:

R¹ is H, CONH₂, T_((n))-R, or T_((n))-Ar²; R is an aliphatic orsubstituted aliphatic group; n is zero or one; T is C(═O), CO₂, CONH,S(O)₂, S(O)₂NH, COCH₂ or CH₂; each R² is independently selected fromhydrogen, —R, —CH₂OR, —CH₂OH, —CH═O, —CH₂SR, —CH₂S(O)₂ R, —CH₂(C═O)R,—CH₂CH₂CO₂R, —CH₂CO₂H, —CH₂CN, —CH₂NHR, —CH₂N(R)₂, —H═N—OR, —CH═NNHR,—CH═NN(R)₂, —CH═NNHCOR, —CH═NNHCO₂R, —CH═NNHSO₂R, -aryl, -substitutedaryl, —CH₂(aryl), —CH₂(substituted aryl), —CH₂ NHz, —CH₂NHCOR,—CH₂NHCONHR, —CH₂NHCON(R)₂, —CH₂NRCOR, —CH₂ NHCO₂R, —CH₂CONHR,—CH₂CON(R)₂, —CH₂SO₂NH₂, —CH₂ (heterocyclyl), —CH₂ (substitutedheterocyclyl), -(heterocyclyl), or -(substituted heterocyclyl); each R³is independently selected from hydrogen, R, COR, CO²R or S(O)²R; C is Ror Ar¹; Ar¹ is aryl, substituted aryl, arylalkyl, substituted arylalkyl,heterocyclyl, or substituted heterocyclyl, wherein Ar¹ is optionallyfused to a partially unsaturated or fully unsaturated five to sevenmembered ring containing zero to three heteroatoms; Q-NH is

wherein the H of Q-NH is optionally replaced by R³; Ar² is aryl,substituted aryl, heterocyclyl or substituted heterocyclyl, wherein Ar²is optionally fused to a partially unsaturated or fully unsaturated fiveto seven membered ring containing zero to three heteroatoms; whereineach substitutable carbon atom in Ar², including the fused ring whenpresent, is optionally and independently substituted by halo, R, OR, SR,OH, NO₂, CN, NH₂, NHR, N(R)₂, NHCOR, NHCONHR, NHCON(R)₂, NRCOR, NHCO₂R,CO₂R, CO₂H, COR, CONHR, CON(R)₂, S(O)R, SONH₂, S(O)R, SO₂NHR, orNHS(O)₂R, and wherein each saturated carbon in the fused ring is furtheroptionally and independently substituted by ═O, ═S, ═NNHR, ═NNR₂, ═N—OR,═NNHCOR, ═NNHCO₂R, ═NNHSO₂R, or ═NR; and wherein each substitutablenitrogen atom in Ar² is optionally substituted by R, COR, S(O)₂R, orCO₂R. These compounds have been described in U.S. Pat. No. 6,693,108,and all of which or any present or future corresponding U.S. applicationor patent are hereby incorporated by reference. Preferred embodimentsinclude:

Further illustrative embodiments can be found in the identifiedreference.

The following derivatives are contemplated for use as therapeutics intreating type I diabetes:

wherein: A and B are each independently selected from N or CH; R¹ and R²are each independently selected from halogen, CN, NO₂, N(R)₂, OR, SR, or(T)_(n)-R⁵; R³ is selected from a 3-6 membered carbocyclic orheterocyclic ring having one to two heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, phenyl, or a 5-6 membered heteroarylring having one to three heteroatoms independently selected fromnitrogen, oxygen, or sulfur, wherein said phenyl or heteroaryl ring isoptionally substituted with one (T)_(n)-Ar and one to two R⁷; each n isindependently selected from zero or one; T is a C₁-C₆ alkylidene chain,wherein one methylene unit of T is optionally replaced by CO, CO₂, COCO,CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO₂, NRCONR, SO₂, NRSO₂, SO₂NR,NRSO₂NR, O, S, or NR; each R is independently selected from hydrogen oran optionally substituted C₁-C₆ aliphatic group; or two R on the samenitrogen atom may be taken together with the nitrogen to form a four toeight membered, saturated or unsaturated heterocyclic ring containingone to three heteroatoms independently selected from nitrogen, oxygen,or sulfur; R⁴ is (T)_(n)-R, (T)_(n)-Ar, or (T)_(n)-Ar¹; R^(a) isselected from R^(b), halogen, NO₂, OR^(b), SR^(b), or N(R^(b))₂; R^(b)is selected from hydrogen or a C₁-C₄ aliphatic group optionallysubstituted with oxo, OH, SH, NH₂, halogen, NO₂, or CN; R⁵ is anoptionally substituted C₁-C₆ aliphatic or Ar; Ar is a 5-6 memberedsaturated, partially unsaturated, or aryl monocyclic ring having zero tothree heteroatoms independently selected from nitrogen, sulfur, oroxygen, or an 8-10-membered saturated, partially unsaturated, or arylbicyclic ring having zero to four heteroatoms independently selectedfrom nitrogen, sulfur, or oxygen, wherein Ar is optionally substitutedwith one to three R⁷; Ar¹ is a 6-membered aryl ring having zero to twonitrogens, wherein said ring is substituted with one Z—R⁶ group andoptionally substituted with one to three R⁷; Z is a C₁-C₆ alkylidenechain wherein up to two nonadjacent methylene units of Z are optionallyreplaced by CO, CO₂, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO₂,NRCONR, SO, SO₂, NRSO₂, SO₂NR, NRSO₂NR, O, S, or NR; provided that saidoptionally replaced methylene unit of Z is a methylene unit non-adjacentto R⁶; R⁶ is selected from Ar, R, halogen, NO₂, CN, OR, SR, N(R)₂,NRC(O)R, NRC(O)N(R)₂, NRCO₂R, C(O)R, CO₂R, OC(O)R, C(O)N(R)₂,OC(O)N(R)₂, SOR, SO₂R, SO₂N(R)₂, NRSO₂R, NRSO₂N(R)₂, C(O)C(O)R, orC(O)CH₂C(O)R; and each R⁷ is independently selected from R, halogen,NO₂, CN, OR, SR, N(R)₂, NRC(O)R, NRC(O)N(R)₂, NRCO₂R, C(O)R, CO₂R,C(O)N(R)₂, OC(O)N(R)₂, SOR, SO₂R, SO₂N(R)₂, NRSO₂R, NRSO₂N(R)₂,C(O)C(O)R, or C(O)CH₂C(O)R; or two R⁷ on adjacent positions of Ar¹ maybe taken together to form a saturated, partially unsaturated, or fullyunsaturated five to seven membered ring containing zero to threeheteroatoms selected from O, S, or N. These compounds have beendescribed in U.S. Patent Application Publication Number 2004/0023963 andall of which or any present or future corresponding U.S. application orpatent are hereby incorporated by reference. Preferred embodimentsinclude:

Further illustrative embodiments can be found in the identifiedreference.

The following derivatives are contemplated for use as therapeutics intreating type I diabetes:

wherein: each W is independently selected from nitrogen or CH; each R¹,R², and R³ is independently selected from halogen, QR, Q_((n))CN,Q_((n))NO₂, or Q_((n))Ar; wherein: R¹ and R² or R² and R³ are optionallytaken together to form a 4-8 membered saturated, partially unsaturated,or fully unsaturated ring having 0-3 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur; n is zero or one; Q is a C₁₋₄alkylidene chain wherein one methylene unit of Q is optionally replacedby O, S, NR, NRCO, NRCONR, NRCO₂, CO, CO₂, CONR, OC(O)NR, SO₂, SO₂NR,NRSO₂, NRSO₂NR, C(O)C(O), or C(O)CH₂C(O); each R is independentlyselected from hydrogen or an optionally substituted C₁-C₄ aliphatic,wherein: two R bound to the same nitrogen atom are optionally takentogether with the nitrogen atom to form a 3-7 membered saturated,partially unsaturated, or fully unsaturated ring having 1-2 additionalheteroatoms independently selected from nitrogen, oxygen, or sulfur; R⁴is Ar¹, T-Ar², or T_((n))-Ar³; T is a C₁₋₂ alkylidene chain wherein onemethylene unit of T is optionally replaced by O, NR, NRCO, NRCONR,NRCO₂, CO, CO2, CONR, OC(O)NR, SO₂, SO₂NR, NRSO₂, NRSO₂NR, C(O)C(O), orC(O)CH₂C(O); Ar¹ is a 5-6 membered monocyclic or 8-10 membered bicyclicsaturated, partially unsaturated, or fully unsaturated ring system;wherein: Ar1 is optionally substituted with up to five substituents,wherein the first substituent is selected from R^(x) or R⁵ and whereinany additional substituents are independently selected from R⁵; eachR^(x) is independently selected from a 5-6 membered aryl ring having 0-3heteroatoms selected from nitrogen, oxygen, or sulfur, wherein: R^(x) isoptionally substituted with 1-3 R⁵; each R⁵ is independently selectedfrom R, halogen, NO₂, CN, OR, SR, N(R)₂, NRC(O)R, NRC(O)N(R)₂, NRCO₂R,C(O)R, CO₂R, C(O)N(R)₂, OC(O)N(R)₂, SOR, SO₂R, SO₂N(R)₂, NRSO₂R,NRSO2N(R)₂, C(O)C(O)R, or C(O)CH₂C(O)R; Ar² is a 5-6 membered saturated,partially unsaturated, or fully unsaturated monocyclic ring having 0-3heteroatoms independently selected from nitrogen, oxygen, or sulfur, oran 8-10 membered saturated, partially unsaturated, or fully unsaturatedbicyclic ring system having 0-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur; wherein: Ar2 is optionally substituted withup to five substituents, wherein the first substituent is selected fromR^(x) or R⁵ and wherein any additional substituents are independentlyselected from R⁵; Ar³ is a 6-membered aryl ring having 0-2 nitrogens,wherein: Ar³ is substituted with one Z—R group and optionallysubstituted with 1-3 R⁵; Z is a C₁-C₆ alkylidene chain wherein up to twonon adjacent methylene units of Z are optionally replaced by CO, CO₂,COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO₂, NRCONR, SO, SO₂, NRSO₂,SO₂NR, NRSO₂NR, O, S, or NR; and R⁶ is selected from Ar², R, halogen,NO₂, CN, OR, SR, N(R)₂, NRC(O)R, NRC(O)N(R)₂, NRCO₂R, C(O)R, CO₂R,OC(O)R, C(O)N(R)₂, OC(O)N(R)₂, SOR, SO₂R, SO₂N(R)₂, NRSO₂R, NRSO₂N(R)₂,C(O)C(O)R, or C(O)CH₂C(O)R. These compounds have been described inInternational Publication Number WO 2002/079197 and all of which or anypresent or future corresponding U.S. application or patent are herebyincorporated by reference. Preferred embodiments include:

Further illustrative embodiments can be found in the identifiedreference.

The following derivatives are contemplated for use as therapeutics intreating type I diabetes:

wherein R¹ is —F, —Cl, —Br, —OH, —SH, —NH₂, or —CH₃; R² is —F, —Cl, —Br—OH, —SH, —NH₂, or —CH₃; R³ is —H, —F, —Cl, —Br, —OH, —SH, —NH₂, —CH₃,—OCH₃, or —CH₂CH₃; R⁴ is —C₁₋₄ alkyl optionally substituted with a —C₃₋₇cycloalkyl; R⁵ is —C₁₋₄ alkyl or —C₃₋₇ cycloalkyl, wherein the —C₁₋₄alkyl is optionally substituted with a phenyl; X is a bond or an alkylbridge having 1-3 carbons; Y is —NH— or —NH₂+—; and HETCy is a 4 to 10membered non-aromatic heterocycle containing at least one N atom,optionally containing 1-2 additional N atoms and 0-10 or S atom, andoptionally substituted with —C₁₋₄ alkyl or —C(O)—O—CH₂-phenyl. Thesecompounds have been described in International Publication Number WO2001/091749 and all of which or any present or future corresponding U.S.application or patent are hereby incorporated by reference. Preferredembodiments include:

Further illustrative embodiments can be found in the correspondingidentified reference.

The embodiments of the current invention are not limited to compoundswith the structures provide. JNK2 inhibitors and selective JNK2inhibitors can be made using organic synthesis techniques known to thoseskilled in the art, as well as by the methods described in therespective identified references.

JNK2 Assays

Proteins can be purified by expressing the amino acid sequence (i.e.,JNK2) in a host, such as E. coli. The protein may be expressed incombination with a second amino acid sequence (fusion-proteins) that hasproperties preferential for purification. For example, The GlutathioneS-transferase (GST) gene fusion system is an integrated system for theexpression, purification and detection of fusion proteins produced inbacterial, yeast, mammalian and insect cells.

The sequence encoding the GST protein is incorporated into an expressionvector, generally upstream of the multi-cloning site. The sequenceencoding the protein of interest is then cloned into this vector.Induction of the vector results in expression of a fusion protein—theprotein of interest fused to the GST protein. The fusion protein canthen be released from the cells and purified.

Purification of the fusion protein is facilitated by the affinity of theGST protein for glutathione residues. Glutathione residues are coupledto a resin and the expressed protein product is brought into contactwith the resin. The fusion protein will bind to the glutathione-resincomplex and all other non-specific proteins can be washed off. Thefusion protein can then be released from the resin using a mild elutionbuffer that is of low pH. Similarly, poly-histidine sequences (his-tags)can be used.

It is possible to remove the GST or his-tag from the protein of interestby using a number of different enzymes (thrombin, factor X), whichcleave specific sites between the GST or his-tag and the protein ofinterest. Fusion proteins can also be detected easily, with a number ofantibodies now available on the market.

There are many well-known methods to one skilled in the art fordetermining the binding of one protein to another. One or more of thefollowing methods and other methods well-known to those skilled in theart can be used to determine whether a compound is an inhibitor JNK2 orselective inhibitor of JNK2.

For example, to 10 μL of 5-amino-anthra(9,1-cd)isothiazol-6-one in 20%DMSO/80% dilution buffer containing of 20 mM HEPES (pH 7.6), 0.1 mMEDTA, 2.5 mM magnesium chloride, 0.004% Triton×100, 2 μg/mL leupeptin,20 mM β-glycerolphosphate, 0.1 mM sodium vanadate, and 2 mM DTT in wateris added 30 μL of 50-200 ng His6-JNK2 in the same dilution buffer. Themixture is pre-incubated for 30 minutes at room temperature. Sixty μL of10 μg GST-c-Jun(1-79) in assay buffer consisting of 20 mM HEPES (pH7.6), 50 mM sodium chloride, 0.1 mM EDTA, 24 mM magnesium chloride, 1 mMDTT, 25 mM PNPP, 0.05% Triton×100, 11 μM ATP, and 0.5 μCi γ-32P ATP inwater is added and the reaction is allowed to proceed for 1 hour at roomtemperature. The c-Jun phosphorylation is terminated by addition of 150μL of 12.5% trichloroacetic acid. After 30 minutes, the precipitate isharvested onto a filter plate, diluted with 50 μL of the scintillationfluid and quantified by a counter. The IC₅₀ values are calculated as theconcentration of 5-amino-anthra(9,1-cd)isothiazol-6-one at which thec-Jun phosphorylation is reduced to 50% of the control value. Compoundsthat inhibit JNK2 preferably have an IC₅₀ value ranging 0.01-10 μM inthis assay. 5-Amino-anthra(9,1-cd)isothiazol-6-one has an IC₅₀ accordingto this assay of 1 μM for JNK2 and 400 nM for JNK3. The measured IC₅₀value for 5-amino-anthra(9,1-cd)isothiazol-6-one, as measured by theabove assay, however, shows some variability due to the limitedsolubility of 5-amino-anthra(9,1-cd)isothiazol-6-one in aqueous media.Despite the variability, however, the assay consistently does show that5-amino-anthra(9,1-cd)isothiazol-6-one selectively inhibits JNK2. Thisassay demonstrates that 5-amino-anthra(9,1-cd)isothiazol-6-one, anillustrative JNK2 inhibitor, inhibits JNK2 selectively and, accordingly,is useful for treating or preventing type I diabetes.

In other examples, following pretreatment with JNK2 inhibitor (63-1700nM in Buffer B (20 mM HEPES, 20 mM MgCl₂, 20 mM β-glycerophosphate, pH7.6, containing 500 μM dithiothreitol, 100 μM sodium orthovanadate), JNKactivity is assayed by incubation in Buffer B supplemented with 20 μMATP, 1μCi of [γ-³²P]ATP, and a protein substrate (10 μg of eitherGST-c-Jun, GST-Elk, or GST-ATF2). The reaction is performed for 30 minat 30° C., and then the phosphorylated substrate was separated bySDS-PAGE, visualized by autoradiography, and quantitated by Cerenkovcounting.

C-Jun Reporter Assays

Detection of JNK2 inhibition is also described in United States PatentApplication Publication US 2004/0248886 A1, hereby incorporated byreference. The phosphorylation of c-jun by JNK2 is followed bymonitoring the incorporation of ³³P into c-jun following the protocolbelow. The inhibitory activity of the JNK2 inhibitors, towards c-junphosphorylation through JNK2, is determined by calculatingphosphorylation activity in the presence or absence of JNK2 inhibitor.

JNK2 assays can be performed in 96 well MTT plates: incubation of 0.5 μmof recombinant, pre-activated GST-JNK2 with 1 μg of recombinant,biotinylated GST-c-Jun and 2 μM ³³γ-ATP (2 nCi/μL), in the presence orabsence of JNK2 inhibitor and in a reaction volume of 50 μL containing50 mM Tris-HCl, pH 8.0; 10 mM MgCl₂; 1 mM Dithiothreitol, and 100 μMNa₃VO₄. The incubation is performed for 120 min. at R.T and stopped uponaddition of 200 μL of a solution containing 250 μg ofStreptavidine-coated SPA beads (Amershain, Inc.), 5 mM EDTA, 0.1%TritonX-100 and 50 μM ATP, in phosphate saline buffer.

After incubation for 60 minutes at RT, beads are sedimented bycentrifugation, resuspended in 200 μL of PBS containing 5 mM EDTA, 0.1%Triton X-100 and 50 μM ATP and the radioactivity measured in ascintillation beta counter, following sedimentation of the beads asdescribed above. By replacing biotinylated GST-c Jun with biotinylatedGST-₁ATF₂ or biotinylated myelin basic protein, this assay can be usedto measure inhibition of preactivated p38 and ERK MAP Kinases,respectively. The JNK2 inhibitors display an inhibition (IC₅₀) withregard to JNK2 of less than 10 μM, preferably less than 1 μM and morepreferred less than 0.25 μM.

The phosphorylation of the transcriptional factor, c-jun, by JNK2 in theMAP kinase signal transduction pathway can be followed via atrans-reporting system such as the commercially available PathDetect asprovided in Xu, L. et al., Assess the in-vivo activation of signaltransduction pathways with Pathdetect reporting systems, Strategies2001, 14 (1): 17-19.

A trans-reporting system allows one to follow, via Luciferase activity,the activation status of a fusion trans-activator protein. Thetrans-activator protein consists of the activation domain of thetranscriptional factor of interest (c-jun) fused with a yeasttranscriptional activator, GALA DNA binding domain (dbd). The GAL4 dbdhas the advantage that no known mammalian transcriptional factors bindto it and therefore the background noise of the assay is very low.

In the present case, Hela luciferase reporter-c-Jun (HLR-c-Jun) celllines that constitutively express GAL4-cJun may be used. RecombinantJNK2 and substrates (c-Jun-(1-135), Elk-(307-428), or ATF2-(19-96)) maybe produced in Escherichia coli as GST fusion proteins. For JNK2, theGST portion of the fusion protein may be removed by overnight cleavagewith thrombin (3 units) in Thrombin Cleavage buffer (50 mM Tris, pH 8.0,150 mM NaCl, 5 mM MgCl₂, 2.5 mM CaCl₂, and 1 mM dithiothreitol)

Once, JNK is activated it can induce the phosphorylation of the c-jundomain of the fusion trans-activator protein (GAL4 dbd-cjun) which formsa dimer. The dimer is then is able to bind to a GAL4 upstream activatingsequence (GAL4 UAS) of the reporter that activates Luciferaseexpression. Luciferase expression is detected by luminescence using asimple assay such as Dual-Luciferase Reporter Assay System in whichRenilla is used as a “control reporter”. Inhibition of JNK is observedas a decrease in Luciferase expression and detected by a decrease inluminescence. U.S. Pat. No. 5,744,320, hereby incorporated by reference,describes a Dual-Luciferase Reporter Assay System.

LPS Induced Endotoxin Shock in Mice

Endotoxins are the lipopolysaccharides (LPS) constituents of the outermembrane of Gram-negative bacteria. Response to LPS has been shown toinvolve the activation of different cell populations and to lead to theexpression of various inflammatory cytokines that include tumor necrosisfactor-alpha (TNF-α) and interferon γ (IFN-γ). As LPS is known tostimulate the activation of various MAP kinase pathways, including JNK,the ability of JNK inhibitors can be tested after the JNK signalingpathway has been switched on by a LPS challenge.

The activity as JNK inhibitors of compounds of formula may be assessedafter a LPS challenge using the following protocol: LPS (S.abortus-Galanos Lab-) is injected (200 μg/kg, i.v.) to Male C57BL/6 miceto induce endotoxin shock. Compounds (0.1, 1, 10 mg/kg) or NaCl (200 uM)are injected intravenously (10 mL/kg) 15 min before the LPS challenge.Heparinized blood was obtained from the orbital sinus at different timepoints after the LPS challenge, and the blood was centrifuged at 9'000rpm for 10 min at 4° C. to collect supernatant. Measurement of cytokinesproduction such as TNF-α and IFN-γ by mouse is performed with an ELISAkit such as Duoset DY410 for TNF-α and DY 485 for IFN-γ. Other ELISAassays can be used.

Surface Plasmon Resonance

Real time kinetic studies of the interactions between recombinant JNKproteins (JNK2, JNK3, and kinase-inactive JNK3) and peptide may beperformed on a BIAcore 2000 biosensor. The running and sample dilutionbuffer is 10 mM HEPES, pH 7.4, 150 mM NaCl, 3.4 mM EDTA, 0.005% (v/v)Tween 20. The biotinylated peptide may immobilized onto 3 flow cells ofeach 4-flow cell SA-biosensor chip to achieve ˜20, 40, and 80 resonanceunits (RU). The remaining blank flow cell on each chip measuredbackground interactions.

The binding of proteins to the immobilized peptides is recorded as RU inreal time to provide a sensorgram. Binding profiles are created byinjecting 10 μM JNK2, JNK3, and kinase-inactive JNK3 (JNK3 (kin⁻)) at aflow rate of 20 μl/min. GST-c-Jun-(1-135), GST-Elk-(307-428), andGST-ATF2-(19-96) are injected at 5 μM concentration to approximateconcentrations present during standard in vitro kinase assays.

Pharmaceutical Compositions

The compositions comprising a JNK2 inhibitor include bulk-drugcompositions useful in the manufacture of pharmaceutical compositions(e.g., impure or non-sterile compositions) and pharmaceuticalcompositions (i.e., compositions that are suitable for administration toa patient) that can be used in the preparation of unit dosage forms.Such compositions optionally comprise a prophylactically ortherapeutically effective amount of a prophylactic and/or therapeuticagent disclosed herein or a combination of those agents and apharmaceutically acceptable carrier. Preferably, compositions of theinvention comprise a prophylactically or therapeutically effectiveamount of JNK2 inhibitor and another therapeutic or prophylactic agent,and a pharmaceutically acceptable carrier.

In a specific embodiment, the term “pharmaceutically acceptable” meansapproved by a regulatory agency of the Federal or a state government orlisted in the U.S. Pharmacopeia or other generally recognizedpharmacopeia for use in animals, and more particularly in humans. Theterm “carrier” refers to a diluent, adjuvant, excipient, or vehicle withwhich a JNK2 inhibitor is administered. Such pharmaceutical vehicles canbe liquids, such as water and oils, including those of petroleum,animal, vegetable or synthetic origin, such as peanut oil, soybean oil,mineral oil, sesame oil and the like. The pharmaceutical vehicles can besaline, gum acacia, gelatin, starch paste, talc, keratin, colloidalsilica, urea, and the like. In addition, auxiliary, stabilizing,thickening, lubricating and coloring agents can be used. Whenadministered to a patient, the pharmaceutically acceptable vehicles arepreferably sterile. Water can be the vehicle when the JNK2 inhibitor isadministered intravenously. Saline solutions and aqueous dextrose andglycerol solutions can also be employed as liquid vehicles, particularlyfor injectable solutions. Suitable pharmaceutical vehicles also includeexcipients such as starch, glucose, lactose, sucrose, gelatin, malt,rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate,talc, sodium chloride, dried skim milk, glycerol, propyleneglycol,water, ethanol and the like. The present compositions, if desired, canalso contain minor amounts of wetting or emulsifying agents, or pHbuffering agents.

The present compositions can take the form of solutions, suspensions,emulsion, tablets, pills, pellets, capsules, capsules containingliquids, powders, sustained-release formulations, suppositories,emulsions, aerosols, sprays, suspensions, or any other form suitable foruse. In one embodiment, the pharmaceutically acceptable vehicle is acapsule (see e.g., U.S. Pat. No. 5,698,155).

In a preferred embodiment, the JNK2 inhibitor and optionally atherapeutic or prophylactic agent are formulated in accordance withroutine procedures as pharmaceutical compositions adapted forintravenous administration to human beings. Typically, JNK2 inhibitorsfor intravenous administration are solutions in sterile isotonic aqueousbuffer. Where necessary, the compositions can also include asolubilizing agent. Compositions for intravenous administration canoptionally include a local anesthetic such as lignocaine to ease pain atthe site of the injection. Generally, the ingredients are suppliedeither separately or mixed together in unit dosage form, for example, asa dry lyophilized powder or water free concentrate in a hermeticallysealed container such as an ampoule or sachette indicating the quantityof active agent. Where the JNK2 inhibitor is to be administered byinfusion, it can be dispensed, for example, with an infusion bottlecontaining sterile pharmaceutical grade water or saline. Where the JNK2inhibitor is administered by injection, an ampoule of sterile water forinjection or saline can be provided so that the ingredients can be mixedprior to administration.

Compositions for oral delivery can be in the form of tablets, lozenges,aqueous or oily suspensions, granules, powders, emulsions, capsules,syrups, or elixirs, for example. Orally administered compositions cancontain one or more optional agents, for example, sweetening agents suchas fructose, aspartame or saccharin; flavoring agents such aspeppermint, oil of wintergreen, or cherry; coloring agents; andpreserving agents, to provide a pharmaceutically palatable preparation.Moreover, where in tablet or pill form, the compositions can be coatedto delay disintegration and absorption in the gastrointestinal tractthereby providing a sustained action over an extended period of time.Selectively permeable membranes surrounding an osmotically activedriving compound are also suitable for an orally administered JNK2inhibitor. In these later platforms, fluid from the environmentsurrounding the capsule is imbibed by the driving compound, which swellsto displace the agent or agent composition through an aperture. Thesedelivery platforms can provide an essentially zero order deliveryprofile as opposed to the spiked profiles of immediate releaseformulations. A time delay material such as glycerol monostearate orglycerol stearate can also be used. Oral compositions can includestandard vehicles such as mannitol, lactose, starch, magnesium stearate,sodium saccharine, cellulose, magnesium carbonate, and the like. Suchvehicles are preferably of pharmaceutical grade.

Further, the effect of the JNK2 inhibitor can be delayed or prolonged byproper formulation. For example, a slowly soluble pellet of the JNK2inhibitor can be prepared and incorporated in a tablet or capsule. Thetechnique can be improved by making pellets of several differentdissolution rates and filling capsules with a mixture of the pellets.Tablets or capsules can be coated with a film that resists dissolutionfor a predictable period of time. Even the parenteral preparations canbe made long-acting, by dissolving or suspending the compound in oily oremulsified vehicles which allow it to disperse only slowly in the serum.

Formulations

Pharmaceutical compositions for use in accordance with the presentinvention can be formulated in conventional manner using one or morephysiologically acceptable carriers or excipients.

Thus, the JNK2 inhibitor and optionally the therapeutic or prophylacticagent and their physiologically acceptable salts and solvates can beformulated into pharmaceutical compositions for administration byinhalation or insufflation (either through the mouth or the nose) ororal, parenteral or mucosol (such as buccal, vaginal, rectal,sublingual) administration. In one embodiment, local or systemicparenteral administration is used.

For oral administration, the pharmaceutical compositions can take theform of, for example, tablets or capsules prepared by conventional meanswith pharmaceutically acceptable excipients such as binding agents(e.g., pregelatinised maize starch, polyvinylpyrrolidone orhydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystallinecellulose or calcium hydrogen phosphate); lubricants (e.g., magnesiumstearate, talc or silica); disintegrants (e.g., potato starch or sodiumstarch glycolate); or wetting agents (e.g., sodium lauryl sulphate). Thetablets can be coated by methods well known in the art. Liquidpreparations for oral administration can take the form of, for example,solutions, syrups or suspensions, or they can be presented as a dryproduct for constitution with water or other suitable vehicle beforeuse. Such liquid preparations can be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents (e.g.,sorbitol syrup, cellulose derivatives or hydrogenated edible fats);emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles(e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetableoils); and preservatives (e.g., methyl or propyl-p-hydroxybenzoates orsorbic acid). The preparations can also contain buffer salts, flavoring,coloring and sweetening agents as appropriate.

Preparations for oral administration can be suitably formulated to givecontrolled release of the active compound.

For buccal administration the pharmaceutical compositions can take theform of tablets or lozenges formulated in conventional manner.

For administration by inhalation, the pharmaceutical compositions foruse according to the present invention are conveniently delivered in theform of an aerosol spray presentation from pressurized packs or anebulizer, with the use of a suitable propellant, e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol the dosage unit can be determined byproviding a valve to deliver a metered amount. Capsules and cartridgesof e.g., gelatin for use in an inhaler or insufflator can be formulatedcontaining a powder mix of the compound and a suitable powder base suchas lactose or starch.

The pharmaceutical compositions can be formulated for parenteraladministration by injection, e.g., by bolus injection or continuousinfusion. Formulations for injection can be presented in unit dosageform, e.g., in ampoules or in multi-dose containers, with an addedpreservative. The pharmaceutical compositions can take such forms assuspensions, solutions or emulsions in oily or aqueous vehicles, and cancontain formulatory agents such as suspending, stabilizing and/ordispersing agents. Alternatively, the active ingredient can be in powderform for constitution with a suitable vehicle, e.g., sterilepyrogen-free water, before use.

The pharmaceutical compositions can also be formulated in rectalcompositions such as suppositories or retention enemas, e.g., containingconventional suppository bases such as cocoa butter or other glycerides.

In addition to the formulations described previously, the pharmaceuticalcompositions can also be formulated as a depot preparation. Such longacting formulations can be administered by implantation (for examplesubcutaneously or intramuscularly) or by intramuscular injection. Thus,for example, the pharmaceutical compositions can be formulated withsuitable polymeric or hydrophobic materials (for example as an emulsionin an acceptable oil) or ion exchange resins, or as sparingly solublederivatives, for example, as a sparingly soluble salt.

The invention also provides that a pharmaceutical composition ispackaged in a hermetically sealed container such as an ampoule orsachette indicating the quantity. In one embodiment, the pharmaceuticalcomposition is supplied as a dry sterilized lyophilized powder or waterfree concentrate in a hermetically sealed container and can bereconstituted, e.g., with water or saline to the appropriateconcentration for administration to a patient.

In other embodiments of the invention, radiation therapy agents such asradioactive isotopes can be given orally as liquids in capsules or as adrink. Radioactive isotopes can also be formulated for intravenousinjection. The skilled oncologist can determine the preferredformulation and route of administration.

The pharmaceutical compositions can, if desired, be presented in a packor dispenser device that can contain one or more unit dosage formscontaining the active ingredient. The pack can for example comprisemetal or plastic foil, such as a blister pack. The pack or dispenserdevice can be accompanied by instructions for administration.

In certain preferred embodiments, the pack or dispenser contains one ormore unit dosage forms containing no more than the recommended dosageformulation as determined in the Physician's Desk Reference (56^(th) ed.2002, herein incorporated by reference in its entirety).

Routes of Administration

Methods of administering a JNK2 inhibitor and optionally a therapeuticor prophylactic agent include, but are not limited to, parenteraladministration (e.g., intradermal, intramuscular, intraperitoneal,intravenous and subcutaneous), epidural, and mucosal (e.g., intranasal,rectal, vaginal, sublingual, buccal or oral routes). In a specificembodiment, the JNK2 inhibitor and optionally the prophylactic ortherapeutic agents are administered intramuscularly, intravenously, orsubcutaneously. The JNK2 inhibitor and optionally the prophylactic ortherapeutic agent can also be administered by infusion or bolusinjection and can be administered together with other biologicallyactive agents. Administration can be local or systemic. The JNK2inhibitor and optionally the prophylactic or therapeutic agent and theirphysiologically acceptable salts and solvates can also be administeredby inhalation or insufflation (either through the mouth or the nose). Ina preferred embodiment, local or systemic parenteral administration isused.

In specific embodiments, it can be desirable to administer the JNK2inhibitor locally to the area in need of treatment. This can beachieved, for example, and not by way of limitation, by local infusionduring surgery, topical application, e.g., in conjunction with a wounddressing after surgery, by injection, by means of a catheter, by meansof a suppository, or by means of an implant, said implant being of aporous, non-porous, or gelatinous material, including membranes, such assilastic membranes, or fibers. In one embodiment, administration can beby direct injection at the site (or former site) of an atheroscleroticplaque tissue.

Pulmonary administration can also be employed, e.g., by use of aninhaler or nebulizer, and formulation with an aerosolizing agent, or viaperfusion in a fluorocarbon or synthetic pulmonary surfactant. Incertain embodiments, the JNK2 inhibitor can be formulated as asuppository, with traditional binders and vehicles such astriglycerides.

In another embodiment, the JNK2 inhibitor can be delivered in a vesicle,in particular a liposome.

In yet another embodiment, the JNK2 inhibitor can be delivered in acontrolled release system. In one embodiment, a pump can be used. Inanother embodiment, polymeric materials can be used.

Dosages

The amount of the JNK2 inhibitor that is effective in the treatment orprevention of type I diabetes can be determined by standard researchtechniques. For example, the dosage of the JNK2 inhibitor which will beeffective in the treatment or prevention of type I diabetes can bedetermined by administering the JNK2 inhibitor to an animal in a modelsuch as, e.g., the animal models known to those skilled in the art. Inaddition, in vitro assays can optionally be employed to help identifyoptimal dosage ranges.

Selection of a particular effective dose can be determined (e.g., viaclinical trials) by a skilled artisan based upon the consideration ofseveral factors which will be known to one skilled in the art. Suchfactors include the disease to be treated or prevented, the symptomsinvolved, the patient's body mass, the patient's immune status and otherfactors known by the skilled artisan.

The precise dose to be employed in the formulation will also depend onthe route of administration, and the seriousness of the disease-relatedwasting, and should be decided according to the judgment of thepractitioner and each patient's circumstances. Effective doses can beextrapolated from dose-response curves derived from in vitro or animalmodel test systems.

The dose of a JNK2 inhibitor to be administered to a patient, such as ahuman, is rather widely variable and can be subject to independentjudgment. It is often practical to administer the daily dose of a JNK2inhibitor at various hours of the day. However, in any given case, theamount of a JNK2 inhibitor administered will depend on such factors asthe solubility of the active component, the formulation used, patientcondition (such as weight), and/or the route of administration.

The general range of effective amounts of the JNK2 inhibitor alone or incombination with the prophylactic or therapeutic agent(s) are from about0.001 mg/day to about 1000 mg/day, more preferably from about 0.001mg/day to 750 mg/day, more preferably from about 0.001 mg/day to 500mg/day, more preferably from about 0.001 mg/day to 250 mg/day, morepreferably from about 0.001 mg/day to 100 mg/day, more preferably fromabout 0.001 mg/day to 75 mg/day, more preferably from about 0.001 mg/dayto 50 mg/day, more preferably from about 0.001 mg/day to 25 mg/day, morepreferably from about 0.001 mg/day to 10 mg/day, more preferably fromabout 0.001 mg/day to 1 mg/day. Of course, it is often practical toadminister the daily dose of compound in portions, at various hours ofthe day. However, in any given case, the amount of compound administeredwill depend on such factors as the solubility of the active component,the formulation used, subject condition (such as weight), and/or theroute of administration.

For antibodies, the dosage administered to a patient is typically 0.1mg/kg to 100 mg/kg of the patient's body weight. Preferably, the dosageadministered to a patient is between 0.1 mg/kg and 20 mg/kg of thepatient's body weight, more preferably 1 mg/kg to 10 mg/kg of thepatient's body weight. Generally, human and humanized antibodies have alonger half-life within the human body than antibodies from otherspecies due to the immune response to the foreign polypeptides. Thus,lower dosages of human antibodies and less frequent administration isoften possible.

The invention provides for any method of administrating lower doses ofknown agents (e.g., insulin) than previously thought to be useful forthe prevention or treatment of type I diabetes.

Kits

The invention provides a pharmaceutical pack or kit comprising one ormore containers containing a JNK2 inhibitor and optionally one or moreother prophylactic or therapeutic agents useful for the treatment oftype I diabetes (e.g insulin). The invention also provides apharmaceutical pack or kit comprising one or more containers containingone or more of the ingredients of the pharmaceutical compositions.Optionally associated with such container(s) can be a notice in the formprescribed by a governmental agency regulating the manufacture, use orsale of pharmaceuticals or biological products, which notice reflectsapproval by the agency of manufacture, use or sale for humanadministration; or instructions for the composition's use.

The present invention provides kits that can be used in the abovemethods. In one embodiment, a kit comprises a JNK Inhibitor, in one ormore containers, and optionally one or more other prophylactic ortherapeutic agents useful for the treatment of type I diabetes, in oneor more containers.

Example 1

Spontaneous diabetes is decreased in JNK2-deficient mice. We used thenon-obese diabetic (NOD) mouse model of autoimmune diabetes as disclosedin Delovitch & Singh, The non-obese diabetic mouse as a model ofautoimmune diabetes: immune dysregulation gets the NOD. Immunity 7,727-38 (1997). NOD and NOD/Scid mice were obtained from The JacksonLaboratory (Bar Harbor, Me.). Mapk9−/− mice (Yang, D. D. et al.Differentiation of CD4+ T cells to Th1 cells requires MAP kinase JNK2.Immunity 9, 575-85 (1998)) were back-crossed with NOD mice for 6generations and Jnk2−/+ mice that are homozygous for the 15 Idd NODalleles were identified by PCR genotyping, as described previously (Moraet al., Role of L-selectin in the development of autoimmune diabetes innon-obese diabetic mice. Int Immunol 16, 257-64 (2004)). TheseNOD/Mapk9−/+ mice were back-crossed for an additional four generationsonto the NOD background. NOD/Mapk9−/− mice were obtained by crossingNOD/Mapk9−/+ mice. The Mapk9 genotype was examined by PCR analysis.Blood glucose levels were monitored weekly with a Dex-Glucometer(Bayer). Animals with a blood glucose level higher than 200 mg/dl for 2consecutive weeks were considered diabetic.

The presence of hyperglycemia (blood glucose>200 mg/dl) was examined ina cohort of 32 NOD mice and 28 female NOD/Mapk9−/− mice. The data inFIG. 1 is presented as the % of mice with hyperglycemia. Comparison ofthe spontaneous incidence of disease in female NOD and NOD/Mapk9−/− miceindicated that JNK2-deficiency decreases the cumulative incidence ofdiabetes.

Example 2

JNK2-defiency causes reduced insulitis in NOD mice. We performedhistological analysis of the pancreas. At 13 weeks of age, control NODmice exhibited severe islet infiltration with less than 20% normalislets and greater than 50% of the islets showing invasive anddestructive insulitis. In contrast, more than 70% of the islets inJNK2-deficient mice were not infiltrated and the residual 30% showedmostly peri-insulitis (FIG. 2 a,b). At 30 weeks of age, all the isletsof NOD mice showed severe destructive insulitis, but normalun-infiltrated islets were detected in JNK2-deficient NOD mice. Controlstudies demonstrated that the extent of islet infiltration inJNK1-deficient (Mapk8−/−) NOD mice was similar to wild type NOD mice,indicating a selective role for JNK2 in the regulation of isletinfiltration in NOD mice.

Example 3

JNK2-deficiency causes reduced diabetes in adoptive transfer studies.Autoimmune diabetes can be adoptively transferred to euglycemicrecipients by injection of splenic T cells. In order to examine thediabetogenic potential of T cells from JNK2-deficient mice, T cells fromyoung (13 week old) non-diabetic NOD and NOD/Mapk9−/− mice weretransferred into NOD/Scid recipients. NOD/Scid mice were injectedintravenously with 2×10⁷ total splenocytes and were monitored (14 weeks)for diabetes. NOD mice (7 weeks old males) were irradiated (725 rad) oneday prior to adoptive transfer of 2×10⁷ total splenocytes from recentlydiagnosed diabetic donors by intravenous injection; the mice weremonitored (8 weeks) for diabetes. The incidence of diabetes wassignificantly reduced if recipient mice received splenic T cells fromJNK2-deficient donors compared to control NOD donors (FIG. 3 a). Thisobservation indicates that the generation of beta-cell specificdiabetogenic T cells may be impaired in JNK2-deficient mice.

Example 4

Analysis of the distribution of T cell populations and their activationmarkers in lymph nodes and spleen showed no difference betweennon-diabetic NOD and NOD/Mapk9−/− mice. The presence of T cells ininfiltrated islets was examined by immunohistochemistry on frozenpancreatic sections. Pancreata were fixed in 10% formalin, embedded inparaffin, sectioned and stained with hematoxylin-eosin.Immunohistochemistry was performed using tissue embedded in Tissue-TekOCT and frozen in 2-methylbutane. 5 μm sections were stained withFITC-conjugated antibodies to CD4 and CD8 (PharMingen) and mounted inVectashield with DAPI (Vector Laboratories).

Although the number of infiltrated islets in NOD mice was greater thanthe number of infiltrated islets in NOD/Mapk9−/− mice (FIG. 2), thepercentage of CD4+ and CD8+ T cells within the infiltrated islets wassimilar in NOD and NOD/Mapk9−/− mice (FIG. 4 a). A Th1 (IFN-gamma)environment accelerates the recruitment of islet-specific CD4+ T cellsand also accelerates the onset of diabetes, while a Th2 environmentprotects against autoimmune diabetes. We therefore examined whetherJNK2-deficiency in NOD CD4+ T cells could promote the differentiation ofthese cells into Th2 effector cells. CD4+ T cells were isolated fromnon-diabetic 8-week-old NOD and JNK2-deficient NOD mice and activatedwith immobilized anti-CD3 monoclonal antibody (mAb) and solubleanti-CD28 mAb in the presence of IL-4 (to promote Th2 differentiation)or IL-12 (to promoteTh1 differentiation). After 4 days ofdifferentiation, the cells were washed and re-restimulated withimmobilized anti-CD3 mAb. Culture supernatants were then harvested 24 hlater for analysis of cytokine production. Although IFN-gamma secretionby Th1 cells was not significantly affected in JNK2-deficient mice (FIG.4 a), the production of IL-4 by Th2 cells and Th1 cells wassubstantially increased in these mice compared with wild-type mice (FIG.4 a). Similarly, the secretion of IL-5, another Th2 cytokine, was alsoaugmented in Th2 and Th1 cells from JNK2-deficient mice (FIG. 4 b).

Example 5

To demonstrate that JNK2-deficiency promoted the production of Th2cytokines, we examined the cytokine profile of non-polarized effector(Th0) cells differentiated with anti-CD3 and anti-CD28 mAbs in theabsence of exogenous cytokines. Although IL-4 secretion by wild-type NODTh0 cells was not detected, high levels of IL-4 were produced byJNK2-deficient NOD Th0 cells (FIG. 4A). Furthermore, the amount of IL-5secreted by JNK2-deficient NOD Th0 cells was similar to the high levelproduced by Th2 cells, but no IL-5 production by NOD Th0 cells wasdetected. In addition, the expression of IFN-gamma by Th0 cells fromJNK2-deficient mice was greatly reduced (FIG. 4 b). To test whether thisphenotype was due to an impaired differentiation or to an impairedactivation of effector cells, we examined cytokine production during thedifferentiation (days 3 and 4) of CD4+ T cells in the absence ofexogenous cytokines. IL-4 was detected in cultures of differentiatingJNK2-deficient CD4+ T cells (FIG. 4 b). In contrast, the JNK2-deficientCD4+ T cells produced lower levels of IFN-gamma compared with NOD CD4+ Tcells (FIG. 4 c). Together, these data indicate that JNK2-deficiencycaused an intrinsic polarization of NOD CD4+ T cells towards Th2effectors independently of the cytokine environment. Control studiesdemonstrated that the Th1/2 polarization of CD4+ T cells fromJNK1-deficient (Mapk8−/−) NOD mice was similar to wild-type NOD mice,indicating a selective role for JNK2 in the regulation of CD4+ Tdifferentiation in NOD mice.

Total CD4+ cells were isolated from spleen and lymph nodes by negativeselection using anti-NK1.1 (Pharmigen), anti-CD8 (TB105), anti-Mac1(Pharmingen), and anti-MHC class II (m5/115) mAbs followed by depletionwith magnetic beads. CD4+ T cells were activated (106 cells/ml) withimmobilized anti-CD3 mAb (2C11) (5 μg/ml) and anti-CD28 mAb (Pharmingen)(1 μg/ml) in the presence of medium (for Th0 cells), IL-4 (for Th2cells) (R&D) (103 U/ml) or IL-12 (for Th1 cells) (Genetics Institute)(3.5 ng/ml) for four days. Cells were then extensively washed, countedand equal number of cells were restimulated with immobilized anti-CD3mAb for 24 h when supernatant was harvested. Cytokine production wasdetermine by ELISAs using anti-IL4 or anti-IFN-γ mAb (2 μg/ml),biotinylated anti-IL4 or anti-IFN-γ mAb (1 μg/ml) (Pharmingen),horseradish peroxidase conjugated avidin D (Sigma), peroxidase substrateand reaction stop solutions

Example 6

We also tested whether the resistance of JNK2-deficient NOD mice toinsulitis was exclusively due to the Th2 phenotype of CD4+ T cells orwhether JNK2 could also contribute to islet β cell death. Adoptivetransfer of T cells isolated from diabetic NOD donor mice causes rapiddevelopment of diabetes in sub-lethally irradiated NOD host mice within2 to 4 weeks. We therefore transferred splenocytes from recentlydiagnosed diabetic female NOD mice into irradiated male NOD andNOD/Mapk9−/− mice. The frequency of diabetes caused by the T cellsisolated from diabetic NOD mice was significantly reduced when thesecells were introduced into JNK2-deficient NOD mice compared to controlNOD mice (FIG. 3 b). The JNK2-deficient NOD group of recipient miceexhibited reduced diabetes compared with the control group of NOD miceafter 8 weeks. These data suggest that JNK2-deficiency may also increaseresistance of P3 cells to apoptosis. Although NOD/Mapk9−/− beta cellsand NOD beta cells were found to be equally sensitive to apoptosisinduced by IL-1beta, TNF-alpha, and IFN-gamma in vitro, it is possiblethat JNK2-deficiency might enhance resistance to death induced by otherT cell mediators, including perforin, granzyme, or Fas ligand.

Example 7

Islets are taken from a donor pancreas and transferred into anotherperson. Once implanted, the β-cells in these islets begin to make andrelease insulin. A 5-amino-anthra(9,1-cd)isothiazol-6-one is administerto a subject before, during, or after islet transplant surgery.

1. A method for treating type I diabetes in a subject, comprisingadministering a compound that inhibits activity of JNK2 in the subject.2. The method of claim 1, wherein the compound inhibits enzymaticactivity of JNK2, and has minimal effect on inhibiting enzymaticactivity of JNK1.
 3. The method of claim 1 in which the activity of JNK1is not inhibited.
 4. The method in claim 1, wherein the activity of thecompound does not result in an adverse drug reaction to the subject.5-7. (canceled)
 8. A method of claim 1, wherein the compound has thefollowing formula:

wherein Ar¹ and Ar² are independently from each other substituted orunsubstituted aryl or heteroaryl groups; X is O or S; R¹ is hydrogen ora C₁-C₆ alkyl group, or R¹ forms a substituted or unsubstituted 5-6membered saturated or unsaturated ring with Ar¹; n is an integer from 0to 5, preferably between 1-3 and most preferred 1; Y is an unsubstitutedor a substituted 4-12 membered saturated cyclic or bicyclic alkylcontaining at least one nitrogen atom, whereby one nitrogen atom withinsaid ring is forming a bond with the sulfonyl group thus providing asulfamide.
 9. The method of claim 1, wherein the compounds has thefollowing formula:

wherein Ar¹ and Ar² are independently from each other substituted orunsubstituted aryl or heteroaryl; X is O or S; R¹ is hydrogen or anunsubstituted or substituted C₁-C₆-alkyl group, or R¹ could form asubstituted or unsubstituted 5-6-membered saturated or unsaturated fusedring with Ar¹, or R² and R⁴ form a substituted or unsubstituted5-6-membered saturated or non-saturated ring; R² is hydrogen or asubstituted or unsubstituted C₁-C₆-alkyl group; n is an integer from 0to 5; R³ and R⁴ are independently from each other selected from thegroup comprising or consisting of natural amino acid residues orsynthetic amino acid residues, hydrogen, substituted or unsubstitutedC₁-C₆-alkyl, like trihalomethyl, substituted or unsubstitutedC₁-C₆-alkoxy, NH₂, SH, thioalkyl, aminoacyl, aminocarbonyl, substitutedor unsubstituted C₁-C₆-alkoxycarbonyl, aryl, heteroaryl, substituted orunsubstituted 4-8-membered cyclic alkyl, optionally containing 1-3heteroatoms, carboxyl, cyano, halogen, hydroxy, nitro, acetoxy,aminoacyl, sulfoxy, sulfonyl, C₁-C₆-thioalkoxy, whereby at least one ofR³ and/or R⁴ must be an amino acid residue; R⁵ is H or substituted orunsubstituted C₁-C₆-alkyl; R⁶ is selected from the group comprising orconsisting of H, substituted or unsubstituted C₁-C₆-aliphatic alkyl,substituted or unsubstituted saturated cyclic C₄-C₈-alkyl optionallycontaining 1-3 heteroatoms and optionally fused with an aryl or anheteroaryl; or R⁶ is a substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, whereby said aryl or heteroaryl groups areoptionally substituted with substituted or unsubstituted C₁-C₆-alkyl,like trihalomethyl, substituted or unsubstituted C₁-C₆-alkoxy,substituted or unsubstituted C₂-C₆-alkenyl, substituted or unsubstitutedC₂-C₆-alkynyl, amino, aminoacyl, aminocarbonyl, substituted orunsubstituted C₁-C₆-alkoxycarbonyl, aryl, carboxyl, cyano, halogen,hydroxy, nitro, acetoxy, aminoacyl, sulfoxy, sulfonyl, C₁-C₆-thioalkoxy;or R⁵ and R⁶ taken together could form a substituted or unsubstituted4-8-membered saturated cyclic alkyl or heteroalkyl group.
 10. The methodof claim 1, wherein the compound has the following formula:

wherein Ar¹ and Ar² are independently from each other substituted orunsubstituted aryl or heteroaryl groups; X¹ and X² are independentlyfrom each other O or S; R¹, R², and R³ are independently from each otherhydrogen or a C₁-C₆ alkyl substituent or R¹ forms a substituted orunsubstituted 5-6-membered saturated or unsaturated ring with Ar¹; or R²and R³ form a substituted or unsubstituted 5-6-membered saturated orunsaturated ring; n is an integer from 0 to 5; G is selected from agroup comprising or consisting of an unsubstituted or substituted4-8-membered heterocycle containing at least one heteroatom, or G is asubstituted or unsubstituted C₁-C₆ alkyl group.
 11. The method of claim1, wherein the compound has the following formula:

wherein Z¹¹ and Z¹² each independently represent a carbonyl group, anoxygen atom, a sulfur atom, a methine group which may be substituted, amethylene group which may be substituted or a nitrogen atom which may besubstituted;

represents a double bond or a single bond; R^(1a) represents a hydrogenatom, a C₁-C₆ alkyl group, a phenyl group or a benzyl group; R^(2a),R^(2b) and R^(2c) each independently represent a group selected from thefollowing Substituent Group (a); the ring A represents a benzene ringwhich may have one to three groups selected from the followingSubstituent Group (a), a naphthalene ring which may have one to threegroups selected from the following Substituent Group (a) or a 5- to10-membered aromatic heterocyclic ring which may have one to threegroups selected from the following Substituent Group (a); SubstituentGroup (a) (1) a hydrogen atom, (2) halogen atoms, (3) a nitro group, (4)a hydroxyl group, (5) a cyano group, (6) a carboxyl group, (7) an aminogroup, (8) a formyl group or (9) a group represented by the formula:

wherein X¹ and X² each independently represent a single bond, —CO—,—SO₂— or C₁-C₆-methylene group; X³ represents a single bond, —CO—, —SO₂,—O—, —CO—O— or —O—CO—; R^(3b) represents a C₁-C₆ alkylene group or asingle bond; R^(3a) and R^(3c) represent a hydrogen atom, a C₁-C₆ alkylgroup which may be substituted, a C₂-C₆ alkenyl group which may besubstituted, a C₂-C₆ alkynyl group which may be substituted, a C₃-C₈cycloalkyl group which may be substituted, a C₆-C₁₄ aromatic cyclichydrocarbon group which may be substituted, a 5- to 14-membered aromaticheterocyclic group which may be substituted or a hydrogen atom.
 12. Themethod of claim 1, wherein the compound has the following formula:

wherein A is a direct bond, —(CH₂)_(a)—, —(CH₂)_(b)CH═CH(CH₂)_(c)—, or—(CH₂)_(b)C≡C(CH₂)_(c)—; R¹ is aryl, heteroaryl or heterocycle fused tophenyl, each being optionally substituted with one to four substituentsindependently selected from R³; R² is —R³, —R⁴, —(CH₂)_(b)C(═O)R⁵,—(CH₂)_(b)C(═O)OR⁵, —(CH₂)_(b)C(═O)NR⁵R⁶,—(CH₂)_(b)C(═O)NR₅(CH₂)CC(═O)R⁶, —(CH₂)_(b)NR⁵C(═O)R⁶,—(CH₂)_(b)NR⁵C(═O)NR⁶R⁷, —(CH₂)_(b)NR⁵R⁶, —(CH₂)_(b)OR⁵,—(CH₂)_(b)SO_(d)R⁵ or —(CH₂)_(b)SO₂NR⁵R⁶; a is 1, 2, 3, 4, 5 or 6; b andc are the same or different and at each occurrence independentlyselected from 0, 1, 2, 3 or 4; d is at each occurrence 0, 1 or 2; R³ isat each occurrence independently halogen, hydroxy, carboxy, alkyl,alkoxy, haloalkyl, acyloxy, thioalkyl, sulfinylalkyl, sulfonylalkyl,hydroxyalkyl, aryl, arylalkyl, heterocycle, heterocycloalkyl, —C(═O)OR⁸,—OC(═O)R⁸, —C(═O)NR⁸R⁹, —C(═O)NR⁸OR⁹, —SO₂NR⁸R⁹, —NR⁸SO₂R⁹, —CN, —NO₂,—NR⁸R⁹, —NR⁸C(═O)R⁹, —NR⁸C(═O)(CH₂)_(b)OR⁹, —NR⁸C(═O)(CH₂)_(b)R⁹,—O(CH₂)_(b)NR⁸R⁹, or heterocycle fused to phenyl; R⁴ is alkyl, aryl,arylalkyl, heterocycle or heterocycloalkyl, each being optionallysubstituted with one to four substituents independently selected fromR³, or R⁴ is halogen or hydroxy; R⁵, R⁶ and R⁷ are the same or differentand at each occurrence independently hydrogen, alkyl, aryl, arylalkyl,heterocycle or heterocycloalkyl, wherein each of R⁵, R⁶ and R⁷ areoptionally substituted with one to four substituents independentlyselected from R³; and R⁸ and R⁹ are the same or different and at eachoccurrence independently hydrogen, alkyl, aryl, arylalkyl, heterocycle,or heterocycloalkyl, or R⁸ and R⁹ taken together with the atom or atomsto which they are bonded form a heterocycle, wherein each of R⁸, R⁹, andR⁸ and R⁹ taken together to form a heterocycle are optionallysubstituted with one to four substituents independently selected fromR³.
 13. The method of claim 1, wherein the compound has the followingformula:

wherein R¹ is aryl or heteroaryl optionally substituted with one to foursubstituents independently selected from R⁷; R² is hydrogen; R³ ishydrogen or lower alkyl; R⁴ represents one to four optionalsubstituents, wherein each substituent is the same or different andindependently selected from halogen, hydroxy, lower alkyl and loweralkoxy; R⁵ and R⁶ are the same or different and independently —R⁸,—(CH₂)_(a)C(═O)R⁹, —(CH2)_(a)C(═O)OR⁹, —(CH2)_(a)C(═O)NR⁹R¹⁰,—(CH2)_(a)C(═O)NR⁹(CH2)_(b)C(═O)R¹⁰, —(CH2)_(a)NR⁹C(═O)R¹⁰,(CH2)_(a)NR¹¹C(═O)NR⁹R¹⁰, —(CH2)_(a)NR⁹R¹⁰, —(CH2)_(a)OR⁹,—(CH2)_(a)SO_(c)R⁹ or —(CH2)_(n)SO2NR⁹R¹⁰; or R⁵ and R⁶ taken togetherwith the nitrogen atom to which they are attached to form a heterocycleor substituted heterocycle; R⁷ is at each occurrence independentlyhalogen, hydroxy, cyano, nitro, carboxyl, alkyl, alkoxy, haloalkyl,acyloxy, thioalkyl, sulfinylalkyl, sulfonylalkyl, hydroxyalkyl, aryl,arylalkyl, heterocycle, substituted heterocycle, heterocycloalkyl,—C(═O)OR⁸, —OC(═O)R⁸, —C(═O)NR⁸R⁹, —C(═O)NR⁸OR⁹, —SO_(c)R⁸,—SO_(c)NR⁸R⁹, —NR⁸SOR⁹, —NR⁸R⁹, —NR⁸C(═O)R⁹, —NR⁸C(═O)(CH₂)bOR⁹,—NR⁸C(═O)(CH2)_(b)R⁹, —O(CH2)_(b)NR⁸R⁹, or heterocycle fused to phenyl;R⁸, R⁹, R¹⁰ and R¹¹ are the same or different and at each occurrenceindependently hydrogen, alkyl, aryl, arylalkyl, heterocycle,heterocycloalkyl; or R⁸ and R⁹ taken together with the atom or atoms towhich they are attached to form a heterocycle; a and b are the same ordifferent and at each occurrence independently selected from 0, 1, 2, 3or 4; and c is at each occurrence 0, 1 or
 2. 14. A method of claim 1,wherein the compound has the following formula:

wherein R⁰ is —O—, —S—, —S(O)—, —S(O)₂—, NH or —CH₂—; being: (i)unsubstituted, (ii) monosubstituted and having a first substituent, or(iii) disubstituted and having a first substituent and a secondsubstituent; the first or second substituent, when present, is at the 3,4, 5, 7, 8, 9, or 10 position, wherein the first and second substituent,when present, are independently alkyl, hydroxy, halogen, nitro,trifluoromethyl, sulfonyl, carboxyl, alkoxycarbonyl, alkoxy, aryl,aryloxy, arylalkyloxy, arylalkyl, cycloalkylalkyloxy, cycloalkyloxy,alkoxyalkyl, alkoxyalkoxy, aminoalkoxy, mono-alkylaminoalkoxy,di-alkylaminoalkoxy, —NHR³R⁴, —NH(CH₂)_(n)NR³R⁴, —NH(═O)R⁵, —NHSO₂R⁵,—C(═O)NR³R⁴, or —SO₂NR³R⁴; wherein n is 0-6, R³ and R⁴ are takentogether and represent alkylidene or a heteroatom-containing cyclicalkylidene or R³ and R⁴ are independently hydrogen, alkyl, cycloalkyl,aryl, arylalkyl, cycloalkylalkyl, aryloxyalkyl, alkoxyalkyl, aminoalkyl,mono-alkylaminoalkyl, or di-alkylaminoalkyl; and R⁵ is hydrogen, alkyl,cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl,alkoxycarbonylalkyl, amino, mono-alkylamino, di-alkylamino, arylamino,arylalkylamino, cycloalkylamino, cycloalkylalkylamino, aminoalkyl,mono-alkylaminoalkyl, or di-alkylaminoalkyl.
 15. The method of claim 1,wherein the compound has the following formula:

wherein N¹ is a nitrogen atom optionally having a substituent or ahydrogen atom, X¹ is (i) a carbon atom optionally having substituent(s)or hydrogen atom(s), (ii) an oxygen atom, (iii) a sulfur atom or (iv) anitrogen atom optionally having a substituent or a hydrogen atom, X² is(i) a carbon atom optionally having substituent(s) or hydrogen atom(s),(ii) an oxygen atom, (iii) a sulfur atom or (iv) a nitrogen atomoptionally having a substituent or a hydrogen atom, X³ is (i) a carbonatom or (ii) a nitrogen atom, wherein (1) when X¹ is an oxygen atom or asulfur atom, X² is a carbon atom optionally having substituent(s) orhydrogen atom(s), X³ is a carbon atom and N¹ is a nitrogen atom, (2)when X¹is a nitrogen atom having a substituent or a hydrogen atom and X³is a carbon atom, X2 is a carbon atom optionally having substituent(s)or hydrogen atom(s) and N¹ is a nitrogen atom, (3) when X¹ and X³ areeach a nitrogen atom, X² is a carbon atom optionally havingsubstituent(s) or hydrogen atom(s), and N¹ is a nitrogen atom, (4) whenX¹ is a carbon atom optionally having substituent(s) or hydrogen atom(s)and X² is an oxygen atom or a sulfur atom, X³ is a carbon atom and N¹ isa nitrogen atom, (5) when X¹ is a carbon atom optionally havingsubstituent(s) or hydrogen atom(s) and X³ is a carbon atom, one of N¹and X² is a nitrogen atom, and the other is a nitrogen atom having asubstituent or a hydrogen atom, (6) when X¹ and X² are each a carbonatom optionally having substituent(s) or hydrogen atom(s) and X³ is acarbon atom, N¹ is a nitrogen atom having a substituent or a hydrogenatom, and (7) when X¹ and X² are each a carbon atom optionally havingsubstituent(s) or hydrogen atom(s) and X³ is a nitrogen atom, N¹ is anitrogen atom, ring A optionally further has substituent(s), ring B isan aromatic ring, Y is (i) a carbon atom optionally havingsubstituent(s) or hydrogen atom(s) or (ii) a nitrogen atom, Z is a bond,—NR⁴— (R⁴ is a hydrogen atom or a hydrocarbon group optionally havingsubstituent(s)), an oxygen atom or an optionally oxidized sulfur atom, Wis a bond or a divalent hydrocarbon group optionally havingsubstituent(s), R² is an aromatic group optionally havingsubstituent(s), and R³ is a hydrocarbon group optionally havingsubstituent(s) or a heterocyclic group optionally having substituent(s).16. The method of claim 1, wherein the compound has the followingformula:

wherein: W is nitrogen or CH; G is hydrogen or C₁₋₃ aliphatic whereinone methylene unit of G is optionally replaced by —C(O)—, —C(O)O—,—C(O)NH—, —SO₂—, or —SO₂NH—; A is —N-T_((n))-R, oxygen, or sulfur; R¹ isselected from -T_((n))-R or -T₍₁₎-Ar¹; each n is independently 0 or 1; Tis a C₁₋₄ alkylidene chain wherein one methylene unit of T is optionallyreplaced by —C(O)—, —C(O)O—, —C(O)NH—, —SO₂—, or —SO₂NH—; Ar¹ is a 3-7membered monocyclic saturated, partially saturated or aromatic ringhaving 0-3 heteroatoms independently selected from nitrogen, oxygen, orsulfur, or a 8-10 membered bicyclic saturated, partially saturated oraromatic ring having 0-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, wherein each member of Ar¹ is optionallysubstituted with one —Z—R³ and one to three additional groupsindependently selected from —R, halogen, oxo, —NO₂, —CN, —OR, —SR,—N(R)₂, —NRC(O)R, —NRC(O)N(R)₂, —NRCO₂R, —C(O)R, —CO₂R, —OC(O)R,—C(O)N(R)₂, —OC(O)N(R)₂, —S(O)R, —SO₂R, —SO₂N(R)₂, —NRSO₂R, —NRSO₂N(R)₂,—C(O)C(O)R, or —C(O)CH₂C(O)R; each R is independently selected fromhydrogen or a C₁₋₆ aliphatic, wherein said aliphatic is optionallysubstituted with one to three groups independently selected from oxo,—CO₂R′, —OR′, —N(R′)₂, —SR′, —NO₂, —NR′C(O)R′, —NR′C(O)N(R′)₂,—NR′CO₂R′, —C(O)R′, —OC(O)R′, —C(O)N(R′)₂, —OC(O)N(R′)₂, —S(O)R′,—SO₂R′, —SO₂N(R′)₂, —NR′SO₂R′, —NR′SO₂N(R′)₂, —C(O)C(O)R′,—C(O)CH₂C(O)R′, halogen, or —CN, or two R bound to the same nitrogenatom are taken together with that nitrogen atom to form a five or sixmembered heterocyclic or heteroaryl ring having one to two additionalheteroatoms independently selected from oxygen, nitrogen, or sulfur;each R′ is independently selected from hydrogen or C₁₋₆ aliphatic,wherein said aliphatic is optionally substituted with one to threegroups independently selected from oxo, —CO₂H, —OH, —NH₂, —SH, —NO₂,—NHC(O)H, —NHC(O)NH₂, —NHCO₂H, —C(O)H, —OC(O)H, —C(O)NH₂, —OC(O)NH₂,—S(O)H, —SO₂H, —SO₂NH₂, —NHSO₂H, —NHSO₂NH₂, —C(O)C(O)H, —C(O)CH₂C(O)H,halogen, or —CN, or two R′ bound to the same nitrogen atom are takentogether with that nitrogen atom to form a five or six memberedheterocyclic or heteroaryl ring optionally having one or two additionalheteroatoms independently selected from nitrogen, oxygen, or sulfur; Zis a C₁-C₆ alkylidene chain wherein up to two nonadjacent methyleneunits of Z are optionally replaced by —C(O)—, —C(O)O—, —C(O)C(O)—,—C(O)N(R)—, —OC(O)N(R)—, —N(R)N(R)—, —N(R)N(R)C(O)—, —N(R)C(O)—,—N(R)C(O)O—, —N(R)C(O)N(R)—, —S(O)—, —SO₂—, —N(R)SO₂—, —SO₂N(R)—,—N(R)SO₂N(R)—, —O—, —S—, or —N(R)—; R² is -Q_((n))-Ar²; Ar² is selectedfrom a 3-7 membered monocyclic saturated, saturated or aromatic ringhaving 0-3 heteroatoms independently selected from nitrogen, oxygen, orsulfur, or a 8-10 membered bicyclic saturated, saturated or aromaticring having 0-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur, wherein each member of Ar² is optionally substitutedwith 1-5 groups independently selected from —Z—R³, —R, halogen, oxo,—NO2, —CN, —OR, —SR, —N(R)₂, NRC(O)R, —NRC(O)N(R)₂, —NRCO₂R, —C(O)R,—CO₂R, OC(O)R, —C(O)N(R)₂, —OC(O)N(R)₂, —S(O)R, —SO₂R, SO₂N(R)₂,—N(R)SO₂R, —N(R)SO₂N(R)₂, —C(O)C(O)R, or —C(O)CH₂C(O)R; Q is a C₁₋₃alkylidene chain wherein up to two nonadjacent methylene units of Q areoptionally replaced by —C(O)—, —C(O)O—, —C(O)C(O)—, —C(O)N(R)—,—OC(O)N(R)—, —N(R)N(R)—, —N(R)N(R)C(O)—, —N(R)C(O)—, —N(R)C(O)O—,—N(R)C(O)N(R)—, —S(O)—, —SO₂—, —N(R)SO₂—, —SO₂N(R)—, —N(R)SO₂N(R)—, —O—,—S—, or —N(R)—; R³ is selected from —Ar³, —R, halogen, —NO₂, —CN, —OR,—SR, —N(R)₂, —NRC(O)R, —NRC(O)N(R)₂, —NRCO₂R, —C(O)R, —CO₂R, —OC(O)R,—C(O)N(R)₂, —OC(O)N(R)₂, —SOR, —SO₂R, —SO₂N(R)₂, —NRSO₂R, —NRSO₂N(R)₂,—C(O)C(O)R, or —C(O)CH2C(O)R; and Ar³ is a 5-6 membered saturated,partially saturated, or aromatic ring having 0-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, wherein eachmember of Ar³ is optionally substituted with halogen, oxo, —CN, —NO₂,—R′, —OR′, —N(R′)₂, —N(R′)C(O)R′, N(R′)C(O)N(R′)₂, —N(R′)CO₂R′, —C(O)R′,—CO₂R′, OC(O)R′, —C(O)N(R′)₂, —OC(O)N(R′)₂, or —SO₂R′; provided thatwhen W is nitrogen and: (i) A is —N-T_((n))-R and R2 is a saturated ringor (ii) A is sulfur, then R¹ is other than an optionally substitutedphenyl.
 17. The method of claim 1, wherein the compound has thefollowing formula:

wherein R¹ is optionally substituted carbocyclyl or heterocyclyl group,R² is an optionally substituted five or six membered heterocyclyl groupor an optionally substituted six membered carbocyclyl group, E ishydrogen, halogen cyano, C₁₋₆ alkoxyl or C₁₋₆ alkyl, G is hydrogen,halogen, cyano, C₁₋₆ alkoxy or C₁₋₆ alkyl, and L is hydrogen, halogen,cyano, C₁₋₆ alkoxy or C₁₋₆ alkyl.
 18. The method of claim 1, wherein thecompound has the following formula:

wherein R¹ is an optionally substituted C₃₋₁₆ carbocyclyl or C₃₋₁₂heterocyclyl group, Y is N or C and Z is lone electron pair, hydrogen,C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₁₋₁₂ haloalkyl, C₃₋₁₂carbocyclyl, C₃₋₁₂ heterocyclyl, —(CH₂)_(n)OR², —(CH₂)NR² ₂, —CO₂R²,—COR², —CONR² ₂, wherein the C₁₋₁₂ alkyl group optionally contains oneor more insertions selected from —O—, —N(R²)—, —S—, —SO—, —SO₂—; andeach substitutable nitrogen atom in Z is optionally substituted by —R³,—COR³, —SO₂R³ or —CO₂R³; wherein n is 1 to 6, preferably n is 1, 2, or3; wherein R² is hydrogen, C₁₋₁₂ alkyl, C₃₋₁₆ carbocyclyl or C₃₋₁₂heterocyclyl, C₁₋₁₂ alkylC₃₋₁₆ carbocyclyl, or C₁₋₁₂ alkylC₃₋₁₂heterocyclyl optionally substituted by one or more of C₁₋₆ alkyl,halogen, C₁₋₆ haloalkyl, —OR⁴, —SR⁴, —NO₂, CN, —NR⁴R⁴, —NR⁴COR⁴,—NR⁴CONR⁴R⁴, —NR⁴CO₂R⁴, —CO₂R⁴, —COR⁴, —CONR⁴ ₂, —SO₂R⁴, —SONR⁴ ₂,—SOR⁴, —SO₂NR⁴R⁴, —NR⁴SO₂R⁴, wherein the C₁₋₁₂ alkyl group optionallyincorporates on or two insertions selected for the group consisting of—O—, —N(R⁴)—, —S—, —SO—, —SO₂—, wherein each R⁴ may be the same ordifferent and is defined below; wherein two R² and NR² ₂ may form apartially saturated, unsaturated or fully saturated five to sevenmembered ring containing one to three heteroatoms, optionally andindependently substituted with one or more halogen, C₁₋₁₂ alkyl, C₂₋₁₂alkenyl, C₂₋₁₂ alkynyl, C₁₋₁₂ haloalkyl, C₃₋₁₂ carbocyclyl, C₃₋₁₂heterocyclyl, —OR⁵, —SR⁵, —NO₂, CN, —NR⁵R⁵, —NR⁵COR⁵, —NR⁵CONR⁵R⁵,—NRCO₂R⁵, —CO₂R⁵, —COR⁵, —CONR⁵ ₂, —SO₂R⁵, —SONR⁵ ₂, —SOR⁵, —SO₂NR⁵R⁵,—NR⁵SO₂R⁵; and each saturated carbon in the optional ring is furtheroptionally and independently substituted by ═O, ═S, NNR⁶ ₂, ═N—OR⁶,═NNR⁶COR⁶, ═NNR⁶CO₂R⁶, ═NNSO₂R⁶, or ═NR⁶; wherein R³ is hydrogen, C₁₋₆alkyl, C₁₋₆ haloalkyl, or C₆₋₁₂ aryl; wherein R⁴ is hydrogen, C₁₋₆alkyl, C₁₋₆ haloalkyl, or C₆₋₁₂ aryl; wherein R⁵ is hydrogen, C₁₋₁₂alkyl, C₃₋₁₆ carbocyclyl or C₃₋₁₂ heterocyclyl, optionally substitutedby one or more of C₁₋₆ alkyl, halogen, C₁₋₆ haloalkyl, —OR⁷, —SR⁷, —NO₂,CN, —NR⁷R⁷, —NR⁷COR⁷, —NR⁷CONR⁷R⁷, —NR⁷CO₂R⁷, —CO₂R⁷, —COR⁷, —CONR⁷ ₂,—SO₂R⁷, —SONR⁷ ₂, —SOR⁷, —SO₂NR⁷R⁷, —NR⁷SO₂R⁷; wherein the C₁₋₁₂ alkylgroup optionally incorporates one or two insertions selected from thegroup consisting of —O—, —N(R⁷)—, —S—, —SO—, —SO₂—, wherein each R⁷ maybe the same or different and is defined below; wherein R⁶ is hydrogen,C₁₋₁₂ alkyl, C₃₋₁₆ carbocyclyl or C₃₋₁₂ heterocyclyl, optionallysubstituted by one or more of C₁₋₆ alkyl, halogen, C₁₋₆ haloalkyl, —OR⁷,—SR⁷, —NO₂, CN, —NR⁷R⁷, —NR⁷COR⁷, —NR⁷CONR⁷R⁷, —NR⁷CO₂R⁷, —CO₂R⁷, —COR⁷,—CONR⁷ ₂, —SO₂R⁷, —SONR⁷ ₂, —SOR⁷, —SO₂NR⁷R⁷, —NR⁷SO₂R⁷; wherein theC₁₋₁₂ alkyl group optionally incorporates one or two insertions selectedfrom the group consisting of —O—, —N(R⁷)—, —S—, —SO—, —SO₂—, whereineach R⁷ may be the same or different and is defined below; wherein R⁷ ishydrogen, C₁₋₆ alkyl, or C₁₋₆ haloalkyl; wherein the optionallysubstituted carbocyclyl or heterocyclyl group in R¹ and Z is optionallyand independently fused to a partially saturated, unsaturated or fullysaturated five to seven membered ring containing zero to threeheteroatoms, and each substitutable carbon atom in R¹ or Z, includingthe optional fused ring, is optionally and independently substituted byone or more of halogen, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₁₋₁₂haloalkyl, C₃₋₁₂ carbocyclyl, C₃₋₁₂ heterocyclyl, —(CH₂)_(n)OR¹²,—(CH₂)_(n)NR¹² ₂, —OR¹², —SR¹², —NO₂, CN, —NR¹²R¹², —NR¹²COR¹²,—NR¹²CONR¹²R¹², —NR¹²CO₂R¹², —CO₂R¹², —COR¹², —CONR¹² ₂, —SO₂R¹²,—SONR¹² ₂, —SOR¹², —SO₂NR¹²R¹², —NR²SO₂R¹²; wherein the C₁₋₁₂ alkylgroup optionally contains one or more insertions selected from —O—,—N(R¹²)—, —S—, —SO—, —SO₂—, and each saturated carbon in the optionallyfused ring is further optionally and independently substituted by ═O,═S, NNR¹³ ₂, ═N—OR¹³, ═NNR¹³COR¹³, ═NNR¹³CO₂R¹³, ═NNSO₂R¹³, or ═NR¹³;and each substitutable nitrogen atom in R¹ is optionally substituted by—R¹⁴, —COR¹⁴, —SO₂R¹⁴, or —CO₂R¹⁴; wherein n is 1 to 6, preferably n is1, 2, or 3; wherein R¹² is hydrogen, C₁₋₁₂ alkyl, C₃₋₁₆ carbocyclyl orC₃₋₁₂ heterocyclyl, optionally substituted by one or more of C₁₋₆ alkyl,halogen, C₁₋₆ haloalkyl, —OR¹⁵, —SR¹⁵, —NO₂, CN, —NR¹⁵R¹⁵, —NR¹⁵COR¹⁵,—NR¹⁵CONR¹⁵R¹¹, —NR¹⁵CO₂R¹⁵, —CO₂R¹⁵, —COR¹⁵, —CONR¹⁵ ₂, —SO₂R¹⁵,—SONR¹⁵ ₂, —SOR¹⁵, —SO₂NR¹⁵R¹⁵, —NR¹⁵SO₂R¹⁵; wherein the C₁₋₁₂ alkylgroup optionally incorporates one or two insertions selected from thegroup consisting of —O—, —N(R¹⁵)—, —S—, —SO—, —SO₂—, wherein each R⁷ maybe the same or different and is defined below; wherein two R¹² and NR¹²₂ may form a partially saturated, unsaturated or fully saturated five toseven membered ring containing one to three heteroatoms, optionally andindependently substituted with one or more halogen, C₁₋₁₂ alkyl, C₂₋₁₂alkenyl, C₂₋₁₂ alkynyl, C₁₋₁₂ haloalkyl, C₃₋₁₂-carbocyclyl, C₃₋₁₂heterocyclyl, —OR¹⁶, —SR¹⁶, —NO₂, CN, —NR¹⁶R¹⁶, —NR¹⁶COR¹⁶,—NR¹⁶CONR⁶R⁶, —NR¹⁶CO₂R¹⁶, —CO₂R¹⁶, —COR¹⁶, —CONR¹⁶ ₂, —SO₂R¹⁶, —SONR¹⁶₂, —SOR¹⁶, —SO₂NR¹⁶R¹⁶, —NR¹⁶SO₂R¹⁶; and each saturated carbon in theoptional ring is further optionally and independently substituted by ═O,═S, NNR¹⁷ ₂, ═N—OR⁷, ═NNR¹⁷COR¹⁷, ═NNR¹⁷CO₂R¹⁷, ═NNSO₂R¹⁷, or ═NR¹⁷;wherein R¹³ is hydrogen, C₁₋₁₂ alkyl, C₃₋₁₆ carbocyclyl or C₃₋₁₂heterocyclyl, optionally substituted by one or more of C₁₋₆ alkyl,halogen, C₁₋₆ haloalkyl, —OR¹⁵, —SR¹⁵, —NO₂, CN, —NR¹⁵R¹⁵, —NR¹⁵COR¹⁵,—NR¹⁵CONR¹⁵R¹⁵, —NR¹⁵CO₂R¹⁵, —CO₂R¹⁵, —COR¹⁵, —CONR¹⁵ ₂, —SO₂R¹⁵,—SONR¹⁵ ₂, —SOR¹⁵, —SO₂NR¹⁵R¹⁵, —NR¹⁵SO₂R¹⁵; wherein the C₁₋₁₂ alkylgroup optionally incorporates one or two insertions selected from thegroup consisting of —O—, —N(R¹⁵)—, —S—, —SO—, —SO₂—, wherein each R¹⁵may be the same or different and is defined below; wherein R¹⁴ ishydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, or C₆₋₁₂ aryl; wherein R¹⁵ ishydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl; wherein R¹⁶ is hydrogen, C₁₋₁₂alkyl, C₃₋₁₆ carbocyclyl or C₃₋₁₂ heterocyclyl, optionally substitutedby one or more of C₁₋₆ alkyl, halogen, C₁₋₆ haloalkyl, —OR¹⁸, —SR¹⁸,—NO₂, CN, —NR¹⁸R¹⁸, —NR¹⁸COR¹⁸, —NR¹⁸CONR¹⁸CONR¹⁸, —NR¹⁸CO₂R¹⁸, —CO₂R¹⁸,—COR¹⁸, —CONR¹⁸ ₂, —SO₂R¹⁸, —SONR¹⁸ ₂, —SOR¹⁸, —SO₂NR¹⁸R¹⁸, —NR¹⁸SO₂R¹⁸;wherein the C₁₋₁₂ alkyl group optionally incorporates one or twoinsertions selected from the group consisting of —O—, —N(R¹⁸)—, —S—,—SO—, —SO₂—, wherein each R¹⁸ may be the same or different and isdefined below; wherein R¹⁷ is hydrogen, C₁₋₁₂ alkyl, C₃₋₁₆ carbocyclylor C₃₋₁₂ heterocyclyl, optionally substituted by one or more of C₁₋₆alkyl, halogen, C₁₋₆ haloalkyl, —OR¹⁸, —SR¹⁸, —NO₂, CN, —NR¹⁸R¹⁸,—NR¹⁸COR¹⁸, —NR¹⁸CONR¹⁸R¹⁸, —NR¹⁸CO₂R¹⁸, —CO₂R¹⁸, —COR¹⁸, —CONR¹⁸ ₂,—SO₂R¹⁸, —SONR¹⁸ ₂, —SOR¹⁸, —SO₂NR¹⁸R¹⁸, —NR¹⁸SO₂R¹⁸; wherein the C₁₋₁₂alkyl group optionally incorporates one or two insertions selected fromthe group consisting of —O—, —N(R¹⁸)—, —S—, —SO—, —SO₂—, wherein each R⁸may be the same or different and is defined below; wherein R¹⁸ ishydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl.
 19. A method of claim 1, whereinthe compound has the following formula:

wherein ring A is an optionally substituted benzene ring, X is —O—, —N═,—NR³— or —CHR³—, R² is an acyl group, an optionally esterified orthioesterified carboxyl group, and optionally substituted carbamoylgroup or an optionally substituted amino group and the line, a brokenline shows a single bond or a double bond, and R¹ is a hydrogen atom,optionally substituted hydrocarbon group, and optionally substitutedheterocyclic group and the like.
 20. A method of claim 1, wherein thecompound has the following formula:

wherein each of Ar^(a) and Ar^(b) is an aromatic group optionally havingsubstituents, Ar^(a) and Ar^(b) optionally form a condensed cyclic grouptogether with the adjacent carbon atom; ring B^(a) is anitrogen-containing heterocycle optionally having substituents; X^(a)and Y^(a) are the same or different and each is (1) a bond, (2) anoxygen atom, (3) S(O)_(p) (wherein p is an integer of 0 to 2), (4)NR^(d) (wherein R^(d) is a hydrogen atom or a lower alkyl group) or (5)a divalent linear lower hydrocarbon group optionally having substituentsand containing 1 to 3 hetero atom(s); ring A^(a) is a 5-membered ringoptionally having substituents; R^(a) and R^(b) are the same ordifferent and each is (1) a hydrogen atom, (2) a halogen atom, (3) ahydrocarbon group optionally having substituents, (4) an acyl group or(5) a hydroxy group optionally having a substituent; R^(c) is (1) ahydrogen atom, (2) a hydroxy group optionally substituted by a loweralkyl group or (3) a carboxyl group.